Benzothiazepine derivatives

ABSTRACT

The present invention relates to compounds of formula (I), wherein variable groups are as defined within; pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as ileal bile acid transport (IBAT) inhibitors for the treatment of hyperlipidaemia. Processes for their manufacture and pharmaceutical compositions containing them are also described.

[0001] This invention relates to benzothiazepine derivatives, orpharmaceutically acceptable salts, solvates, solvates of such salts andprodrugs thereof. These benzothiazepines possess ileal bile acidtransport (IBAT) inhibitory activity and accordingly have value in thetreatment of disease states associated with hyperlipidaemic conditionsand they are useful in methods of treatment of a warm-blooded animal,such as man. The invention also relates to processes for the manufactureof said benzothiazepine derivatives, to pharmaceutical compositionscontaining them and to their use in the manufacture of medicaments toinhibit IBAT in a warm-blooded animal, such as man.

[0002] It is well-known that hyperlipidaemic conditions associated withelevated concentrations of total cholesterol and low-density lipoproteincholesterol are major risk factors for cardiovascular atheroscleroticdisease (for instance “Coronary Heart Disease: Reducing the Risk; aWorldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999,100, 1930-1938 and “Diabetes and Cardiovascular Disease: A Statement forHealthcare Professionals from the American Heart Association” Grundy S,Benjamin I, Burke G., et al; Circulation, 1999, 100, 1134-46).Interfering with the circulation of bile acids within the lumen of theintestinal tracts is found to reduce the level of cholesterol. Previousestablished therapies to reduce the concentration of cholesterolinvolve, for instance, treatment with HMG-CoA reductase inhibitors,preferably statins such as simvastatin and fluvastatin, or treatmentwith bile acid binders, such as resins. Frequently used bile acidbinders are for instance cholestyramine and cholestipol. One recentlyproposed therapy (“Bile Acids and Lipoprotein Metabolism: a Renaissancefor Bile Acids in the Post Statin Era” Angelin B, Eriksson M, Rudling M;Current Opinion on Lipidology, 1999, 10, 269-74)involved the treatmentwith substances with an IBAT inhibitory effect.

[0003] Re-absorption of bile acid from the gastro-intestinal tract is anormal physiological process which mainly takes place in the ileum bythe IBAT mechanism. Inhibitors of IBAT can be used in the treatment ofhypercholesterolaemia (see for instance “Interaction of bile acids andcholesterol with nonsystemic agents having hypocholesterolaemicproperties”, Biochemica et Biophysica Acta, 1210 (1994) 255-287). Thus,suitable compounds having such inhibitory IBAT activity are also usefulin the treatment of hyperlipidaemic conditions.

[0004] Compounds possessing such IBAT inhibitory activity have beendescribed, see for instance the compounds described in WO 93/16055, WO94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/50051 and EP 0864 582.

[0005] A further aspect of this invention relates to the use of thecompounds of the invention in the treatment of dyslipidemic conditionsand disorders such as hyperlipidaemia, hypertrigliceridemia,hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (highVLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia,hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). Inaddition, these compounds are expected to be useful for the preventionand treatment of different clinical conditions such as atherosclerosis,arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vasculardysfunction, endothelial dysfunction, heart failure, coronary heartdiseases, cardiovascular diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, inflammation of cardiovasculartissues such as heart, valves, vasculature, arteries and veins,aneurisms, stenosis, restenosis, vascular plaques, vascular fattystreaks, leukocytes, monocytes and/or macrophage infiltration, intimalthickening, medial thinning, infectious and surgical trauma and vascularthrombosis, stroke and transient ischaemic attacks.

[0006] The present invention is based on the discovery that certainbenzothiazepine compounds surprisingly inhibit IBAT. Such properties areexpected to be of value in the treatment of disease states associatedwith hyperlipidaemic conditions.

[0007] Accordingly, the present invention provides a compound of formula(I):

[0008] wherein:

[0009] R^(v) and R^(w) are independently selected from hydrogen orC₁₋₆alkyl;

[0010] One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and theother is selected from C₁₋₆alkyl;

[0011] R^(x) and R^(y) are independently selected from hydrogen orC₁₋₆alkyl, or one of R^(x) and R^(y) is hydrogen or C₁₋₆alkyl and theother is hydroxy or C₁₋₆alkoxy;

[0012] R^(z) is selected from halo, nitro, cyano, hydroxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl;

[0013] v is 0-5;

[0014] one of R⁴ and R⁵ is a group of formula (IA):

[0015] R³ and R⁶ and the other of R⁴ and R⁵ are independently selectedfrom hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁷;

[0016] X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

[0017] Ring A is aryl or heteroaryl; wherein Ring A is optionallysubstituted on carbon by one or more substituents selected from R¹⁸;

[0018] R⁷ is hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl; whereinR⁷ is optionally substituted on carbon by one or more substituentsselected from R¹⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R²⁰;

[0019] R⁸ is hydrogen or C₁₋₆alkyl;

[0020] R⁹ is hydrogen or C₁₋₆alkyl;

[0021] R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino, N,N,N—(C₁₋₁₀alkyl)₃ammonio,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²¹—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²²—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁰is optionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁴; orR¹⁰ is a group of formula (IB):

[0022] wherein:

[0023] R¹¹ is hydrogen or C₁₋₆alkyl;

[0024] R¹² and R¹³ are independently selected from hydrogen, halo,nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N-C₁₋₁₀alkyl)sulphamoyl,N,N-C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, carbocyclyl or heterocyclyl; whereinR¹² and R¹³ may be independently optionally substituted on carbon by oneor more substituents selected from R²⁵; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R²⁶;

[0025] R¹⁴ is selected from hydrogen, halo, nitro, cyano, hydroxy,amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N-C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N-)₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²⁷—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-C₁₋₁₀alkylene)_(r)-R²⁸—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁴may be optionally substituted on carbon by one or more substituentsselected from R²⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁰; or R¹⁴ is a group of formula (IC):

[0026] R¹⁵ is hydrogen or C₁₋₆alkyl;

[0027] R¹⁶ is hydrogen or C₁₋₆alkyl; wherein R¹⁶ may be optionallysubstituted on carbon by one or more groups selected from R³¹;

[0028] n is 1-3; wherein the values of R⁷ may be the same or different;

[0029] R¹⁷, R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ are independently selectedfrom halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,sulphamoyl, hydroxyaminocarbonyl, amidino, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,(C₁₋₁₀alkyl)₃silyl, N-C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N-C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R³²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R³³—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁷,R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³ may be independently optionallysubstituted on carbon by one or more R³⁴; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁵;

[0030] R²¹, R²², R²⁷, R²⁸ R³²or R³³ are independently selected from —O—,—NR³⁶—, —S(O)_(x)—, —NR³⁶C(O)NR³⁶—, —NR³⁶C(S)NR³⁶—, —OC(O)N═C—,—NR³⁶C(O)— or —C(O)NR³⁶—; wherein R³⁶ is selected from hydrogen orC₁₋₆alkyl, and x is 0-2;

[0031] p, q, r and s are independently selected from 0-2;

[0032] R³⁴ is selected from halo, hydroxy, cyano, carbamoyl, ureido,amino, nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,formyl, acetyl, formamido, acetylamino, acetoxy, methylamino,dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio,methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl,N-methylsulphamoylamino and N,N-dimethylsulphamoylamino;

[0033] R²⁰, R²⁴, R²⁶, R³⁰ or R³⁵ are independently selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof.

[0034] Accordingly, in another aspect of the present invention there isprovided a compound of formula (I):

[0035] wherein:

[0036] One of R¹ and R² are selected from hydrogen or C ₁₋₆alkyl and theother is selected from C₁₋₆alkyl;

[0037] R^(z) is selected from halo, nitro, cyano, hydroxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl;

[0038] v is 0-5;

[0039] one of R⁴ and R⁵ is a group of formula (IA):

[0040] R³ and R⁶ and the other of R⁴ and R⁵ are independently selectedfrom hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁷;

[0041] X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

[0042] Ring A is aryl or heteroaryl; wherein Ring A is optionallysubstituted on carbon by one or more substituents selected from R¹⁸;

[0043] R⁷ is hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl; whereinR⁷ is optionally substituted on carbon by one or more substituentsselected from R¹⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R²⁰;

[0044] R⁸ is hydrogen or C₁₋₆alkyl;

[0045] R⁹ is hydrogen or C₁₋₆alkyl;

[0046] R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino, N,N,N—(C₁₋₁₀alkyl)₃ammonio,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀allyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²¹—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²²—(C₁₋₁₀alkylene)s-; wherein R¹⁰ isoptionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁴; orR¹⁰ is a group of formula (IB):

[0047] wherein:

[0048] R¹¹ is hydrogen or C₁₋₆alkyl;

[0049] R¹² and R¹³ are independently selected from hydrogen, halo,nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, carbocyclyl or heterocyclyl; whereinR¹² and R¹³ may be independently optionally substituted on carbon by oneor more substituents selected from R²⁵; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R²⁶;

[0050] R¹⁴ is selected from hydrogen, halo, nitro, cyano, hydroxy,amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²⁷—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²⁸—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁴may be optionally substituted on carbon by one or more substituentsselected from R²⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁰; or R¹⁴ is a group of formula (IC):

[0051] R¹⁵ is hydrogen or C₁₋₆allyl;

[0052] R¹⁶ is hydrogen or C₁₋₆alkyl; wherein R¹⁶ may be optionallysubstituted on carbon by one or more groups selected from R³¹;

[0053] n is 1-3; wherein the values of R⁷ may be the same or different;

[0054] R¹⁷, R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ are independently selectedfrom halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N-C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino, N,N,N—(C₁₋₁₀alkyl)₃ammonio,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N-C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R³²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R³³—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁷,R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³ may be independently optionallysubstituted on carbon by one or more R³⁴; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁵;

[0055] R²¹, R²², R²⁷, R²⁸, R³² or R³³ are independently selected from—O—, —NR³⁶—, —S(O )_(x)—, —NR³⁶C(O)NR³⁶—, —NR³⁶C(S)NR³⁶—, —OC(O)N═C—,—NR³⁶C(O)— or —C(O)NR³⁶—; wherein R³⁶ is selected from hydrogen orC₁₋₆alkyl, and x is 0-2;

[0056] p, q, r and s are independently selected from 0-2;

[0057] R³⁴ is selected from halo, hydroxy, cyano, carbamoyl, ureido,amino, nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,formyl, acetyl, formamido, acetylamino, acetoxy, methylamino,dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio,methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl,N-methylsulphamoylamino and N,N-dimethylsulphamoylamino;

[0058] R²⁰, R²⁴, R²⁶, R³⁰ or R³⁵ are independently selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof.

[0059] In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” includes C₁₋₄alkyl, C₁₋₃alkyl, propyl, isopropyland t-butyl. However, references to individual alkyl groups such as‘propyl’ are specific for the straight chained version only andreferences to individual branched chain alkyl groups such as ‘isopropyl’are specific for the branched chain version only. A similar conventionapplies to other radicals, for example “phenylC₁₋₆alkyl” would includephenylC₁₋₆alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term“halo” refers to fluoro, chloro, bromo and iodo.

[0060] Where optional substituents are chosen from “one or more” groupsit is to be understood that this definition includes all substituentsbeing chosen from one of the specified groups or the substituents beingchosen from two or more of the specified groups.

[0061] “Heteroaryl” is a totally unsaturated, mono or bicyclic ringcontaining 3-12 atoms of which at least one atom, particularly 1-3atoms, are chosen from nitrogen, sulphur or oxygen, which may, unlessotherwise specified, be carbon or nitrogen linked. Preferably“heteroaryl” refers to a totally unsaturated, monocyclic ring containing5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms of which atleast one atom is chosen from nitrogen, sulphur or oxygen, which may,unless otherwise specified, be carbon or nitrogen linked. Examples andsuitable values of the term “heteroaryl” are thienyl, isoxazolyl,imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyranyl,indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl and quinolyl.Preferably the term “heteroaryl” refers to thienyl or indolyl.“Heteroaryl” is not tetrazolyl.

[0062] “Aryl” is a totally unsaturated, mono or bicyclic carbon ringthat contains 3-12 atoms. Preferably “aryl” is a monocyclic ringcontaining 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.Suitable values for “aryl” include phenyl or naphthyl. Particularly“aryl” is phenyl.

[0063] A “heterocyclyl” is a saturated, partially saturated orunsaturated, mono or bicyclic ring containing 3-12 atoms of which atleast one atom, particularly 1-3 atoms, are chosen from nitrogen,sulphur or oxygen, which may, unless otherwise specified, be carbon ornitrogen linked, wherein a —CH₂— group can optionally be replaced by a—C(O)— or a ring sulphur atom may be optionally oxidised to form theS-oxides. Preferably a “heterocyclyl” is a saturated, partiallysaturated or unsaturated, mono or bicyclic ring containing 5 or 6 atomsof which at least one atom is chosen from nitrogen, sulphur or oxygen,which may, unless otherwise specified, be carbon or nitrogen linked,wherein a —CH₂— group can optionally be replaced by a —C(O)— or a ringsulphur atom may be optionally oxidised to form S-oxide(s). Examples andsuitable values of the term “heterocyclyl” are thiazolidinyl,pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl,2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl,2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl,1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl,4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl,2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl,1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino,1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl,homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl,thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl,indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl,4-pyridonyl, quinolyl and 1-isoquinolonyl. “Heterocyclyl” is nottetrazolyl.

[0064] A “carbocyclyl” is a saturated, partially saturated orunsaturated, mono or bicyclic carbon ring that contains 3-12 atoms;wherein a —CH₂— group can optionally be replaced by a —C(O)—. Preferably“carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclicring containing 9 or 10 atoms. Suitable values for “carbocyclyl” includecyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or1-oxoindanyl. Particularly “carbocyclyl” is cyclopropyl, cyclobutyl,1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,phenyl or 1-oxoindanyl.

[0065] An example of “C₁₋₁₀alkanoyloxy” and “C₁₋₆alkanoyloxy” isacetoxy. Examples of “C₁₋₁₀alkoxycarbonyl” and “C₁₋₆alkoxycarbonyl”include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.Examples of “C₁₋₁₀alkoxy” and “C₁₋₆alkoxy” include methoxy, ethoxy andpropoxy. Examples of “C₁₋₁₀alkanoylamino” and “C₁₋₆alkanoylamino”include formamido, acetamido and propionylamino. Examples of“C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2” and “C₁₋₆alkylS(O)_(a) whereina is 0 to 2” include methylthio, ethylthio, methylsulphinyl,ethylsulphinyl, mesyl and ethylsulphonyl. Examples of “C₁₋₁₀alkanoyl”and “C₁₋₆alkanoyl” include C₁₋₃alkanoyl, propionyl and acetyl. Examplesof “N-C₁₋₁₀alkylamino” and “N-C₁₋₆alkylamino” include methylamino andethylamino. Examples of “N,N—(C₁₋₁₀alkyl)₂amino” and“N,N—(C₁₋₆alkyl)₂amino” include di-N-methylamino, di-(N-ethyl)amino andN-ethyl-N-methylamino. Examples of “C₂₋₁₀alkenyl” and “C₂₋₆alkenyl” arevinyl, allyl and 1-propenyl. Examples of “C₂₋₁₀alkynyl” and“C₂₋₆alkynyl” are ethynyl, 1-propynyl and 2-propynyl. Examples of“N—(C₁₋₁₀alkyl)sulphamoyl” and “N—(C₁₋₆alkyl)sulphamoyl” areN—(C₁₋₃alkyl)sulphamoyl, N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.Examples of “N—(C₁₋₁₀alkyl)₂sulphamoyl” and “N—(C₁₋₆alkyl)₂sulphamoyl”are N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl.Examples of “N—(C₁₋₁₀alkyl)carbamoyl” and “N—(C₁₋₆alkyl)carbamoyl” aremethylaminocarbonyl and ethylaminocarbonyl. Examples of“N,N—(C₁₋₁₀alkyl)₂carbamoyl” and “N,N—(C₁₋₆alkyl)₂carbamoyl” aredimethylaminocarbonyl and methylethylaminocarbonyl. Example of“C₁₋₁₀alkylsulphonyl” and “C₁₋₆alkylsulphonyl” are mesyl andethylsulphonyl. Examples of “N,N,N—(C₁₋₁₀alkyl)₃ammonio” and“N,N,N—(C₁₋₆alkyl)₃ammonio” are trimethylamino and methyldiethylamino.Examples of “C₁₋₁₀alkoxycarbonylamino” and “C₁₋₆alkoxycarbonylamino” aremethoxycarbonylamino and t-butoxycarbonylamino. Examples of“N-C₁₋₁₀alkyl)sulphamoylamino” and “N—(C₁₋₆alkyl)sulphamoyl amino” areN-methylsulphamoylamino and N-ethylsulphamoylamino. Examples of“N,N—(C₁₋₁₀alkyl)₂sulphamoylamino” and “N,N—(C₁₋₆alkyl)₂sulphamoylamino”are N,N-dimethylsulphamoylamino and N-methyl-N-ethylsulphamoylamino.Examples of “C₁₋₁₀alkylthio” and “C₁₋₆alkylthio” are methylthio andethylthio. Examples of “carbocyclylC₁₋₁₀alkyl” include benzyl andphenethyl. Examples of “heterocyclylC₁₋₁₀alkyl” include morphoinopropyland pyridylmethyl. Examples of “(C₁₋₁₀alkyl)₃silyl” are trimethylsilyland triethylsilyl.

[0066] A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric, acetate or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

[0067] The compounds of the formula (I) may be administered in the formof a pro-drug which is broken down in the human or animal body to give acompound of the formula (I). examples of pro-drugs include in vivohydrolysable esters and in vivo hydrolysable amides of a compound of theformula (I).

[0068] An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol. Suitable pharmaceutically acceptableesters for carboxy include C₁₋₆alkoxymethyl esters for examplemethoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

[0069] An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

[0070] A suitable value for an in vivo hydrolysable amide of a compoundof the formula (I) containing a carboxy group is, for example, aN-C₁₋₆alkyl or N,N-di-C₁₋₆alkyl amide such as N-methyl, N-ethyl,N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

[0071] Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess IBAT inhibitoryactivity.

[0072] The invention relates to any and all tautomeric forms of thecompounds of the formula (I) that possess IBAT inhibitory activity.

[0073] It is also to be understood that certain compounds of the formula(I) can exist in solvated as well as unsolvated forms such as, forexample, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which possess IBAT inhibitoryactivity.

[0074] Particular values are as follows. Such values may be used whereappropriate with any of the definitions, claims or embodiments definedhereinbefore or hereinafter.

[0075] R^(v) and R^(w) are both hydrogen.

[0076] R¹ and R² are independently selected from C₁₋₄alkyl.

[0077] One of R¹ and R² is ethyl or propyl and the other is butyl.

[0078] One of R¹ and R² is ethyl and the other is butyl.

[0079] R¹ and R² are both butyl.

[0080] One of R¹ and R² is ethyl and the other is butyl, or R¹ and R²are both butyl.

[0081] R^(x) and R^(y) are independently selected from hydrogen orC₁₋₆alkyl.

[0082] R^(x) and R^(y) are both hydrogen.

[0083] R^(z) is C₁₋₄alkyl.

[0084] v is 0-2.

[0085] v is 0.

[0086] R³ and R⁶ and the other of R⁴ and R⁵ are independently selectedfrom hydrogen and C₁₋₆alkylthio.

[0087] R³ and R⁶ are hydrogen.

[0088] R⁴ is halo.

[0089] R⁴ is bromo or chloro.

[0090] R⁴ is C₁₋₆alkoxy.

[0091] R⁴ is ethoxy or methoxy.

[0092] R⁴ is methoxy.

[0093] R⁴ is ethylthio or methylthio.

[0094] R⁴ is methylthio.

[0095] R⁴ is hydrogen.

[0096] R⁴ is hydrogen or methylthio.

[0097] R⁵ is methylthio.

[0098] R⁴ is a group of formula (IA) as depicted above.

[0099] R⁵ is a group of formula (IA) as depicted above.

[0100] R⁴ is methylthio and R⁵ is a group of formula (IA) as depictedabove.

[0101] R⁵ is methylthio and R⁴ is a group of formula (IA) as depictedabove.

[0102] R⁵ is a group of formula (IA) as depicted above wherein:

[0103] X is —O—;

[0104] R⁷ is hydrogen;

[0105] R⁸ is hydrogen;

[0106] R⁹ is hydrogen;

[0107] Ring A is aryl;

[0108] R¹⁰ is carbamoyl or N—(C₁₋₁₀alkyl)carbamoyl or a group of formula(IB) (as depicted above) wherein R¹⁰ is optionally substituted on carbonby one or more substituents selected from R²³ and wherein:

[0109] R¹¹ is hydrogen;

[0110] R¹² and R¹³ are independently selected from hydrogen, carbamoylor C₁₋₆alkyl; wherein R¹² and R¹³ may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵;

[0111] R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl, C₁₋₆alkyl,carbocyclyl, heterocyclyl orcarbocyclyl-(C₁₋₆alkylene)_(p)-R²⁷—(C₁₋₆alkylene)_(q)-; wherein R¹⁴ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R³⁰; orR¹⁴ is a group of formula (IC) (as depicted above) wherein:

[0112] R¹⁵ is hydrogen;

[0113] R¹⁶ is C₁₋₆alkyl; wherein R¹⁶ may be optionally substituted oncarbon by one or more groups selected from R³¹;

[0114] n is 1;

[0115] R²³ is hydroxy;

[0116] R²⁵, R²⁹ or R³¹ are independently selected from halo, hydroxy,amino, sulphamoyl, C₁₋₆alkoxy, N,N,N—(C₁₋₆alkyl)₃ammonio,N,N—(C₁₋₆alkyl)₂sulphamoylamino, C₁₋₆alkoxycarbonylamino, carbocyclyl,heterocyclyl, carbocyclyl-(C₁₋₆alkylene)_(p)-R³²—(C₁₋₆alkylene)_(q)- orheterocyclyl-(C₁₋₆alkylene)_(r)-R³³—(C₁₋₆alkylene)_(s)-; wherein R²⁵,R²⁹ or R³¹ may be independently optionally substituted on carbon by oneor more R³⁴; and wherein if said heterocyclyl contains an —NH— group,that nitrogen may be optionally substituted by a group selected fromR³⁵;

[0117] R²⁷, R³² or R³³ are independently selected from —O—,—NR³⁶C(O)NR³⁶—, —OC(O)N═C— or —NR³⁶C(O)—; wherein R²³ is hydrogen;

[0118] p, q, r and s are independently selected from 0 or 1;

[0119] R³⁴ is selected from hydroxy, amino, carbamoyl, sulphamoyl ormethoxy;

[0120] R³⁰ or R³⁵ are independently selected from C₁₋₆alkyl orC₁₋₆alkoxycarbonyl.

[0121] R⁵ is a group of formula (IA) as depicted above wherein:

[0122] X is —O—;

[0123] R⁷ is hydrogen;

[0124] R⁸ is hydrogen;

[0125] R⁹ is hydrogen;

[0126] Ring A is aryl; wherein Ring A is optionally substituted oncarbon by one or more substituents selected from R¹⁸;

[0127] R¹¹ is carbamoyl or N—(C₁₋₁₀alkyl)carbamoyl or a group of formula(IB) (as depicted above) wherein R¹⁰ is optionally substituted on carbonby one or more substituents selected from R²³ and wherein:

[0128] R¹¹ is hydrogen or C₁₋₆alkyl;

[0129] R¹² and R¹³ are independently selected from hydrogen, carbamoylor C₁₋₆alkyl; wherein R¹² and R¹³ may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵;

[0130] R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl, C₁₋₆alkyl,carbocyclyl, heterocyclyl orcarbocyclyl-(C₁₋₆alkylene)_(p)-R²⁷—(C₁₋₆alkylene)_(q)-; wherein R¹⁴ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R³⁰; orR¹⁴ is a group of formula (IC) (as depicted above) wherein:

[0131] R¹⁵ is hydrogen;

[0132] R¹⁶ is C₁₋₆alkyl; wherein R¹⁶ may be optionally substituted oncarbon by one or more groups selected from R³¹;

[0133] n is 1;

[0134] R¹⁸ is hydroxy;

[0135] R²³ is hydroxy;

[0136] R²⁵, R²⁹ or R³¹ are independently selected from halo, hydroxy,amino, sulphamoyl, amidino, C₁₋₆alkoxy, N,N,N—(C₁₋₆alkyl)₃ammonio,N,N—(C₁₋₆alkyl)₂sulphamoylamino, C₁₋₆alkoxycarbonylamino, carbocyclyl,heterocyclyl, carbocyclyl-(C₁₋₆alkylene)_(p)-R³²—(C₁₋₆alkylene)_(q)- orheterocyclyl-(C₁₋₆alkylene)_(r)-R³³—(C₁₋₆alkylene)_(s)-; wherein R²⁵,R²⁹ or R³¹ may be independently optionally substituted on carbon by oneor more R³⁴; and wherein if said heterocyclyl contains an —NH— group,that nitrogen may be optionally substituted by a group selected fromR³⁵;

[0137] R²⁷, R³² or R³³ are independently selected from —O—,—NR³⁶C(O)NR³⁶—, —OC(O)N═C— or —NR³⁶C(O)—; wherein R²³ is hydrogen;

[0138] p, q, r and s are independently selected from 0 or 1;

[0139] R³⁴ is selected from hydroxy, amino, carbamoyl, sulphamoyl ormethoxy, R³⁰ or R³⁵ are independently selected from C₁₋₆alkyl orC₁₋₆alkoxycarbonyl. R⁵ is a group of formula (IA) as depicted abovewherein:

[0140] X is —O—;

[0141] R⁷ is hydrogen;

[0142] R⁸ is hydrogen;

[0143] R⁹ is hydrogen;

[0144] Ring A is phenyl;

[0145] R¹⁰ is carbamoyl or a group of formula (IB) (as depicted above)wherein:

[0146] R¹¹ is hydrogen;

[0147] R¹² and R¹³ are independently selected from hydrogen, carbamoylor C₁₋₆alkyl; wherein R¹² and R¹³ may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵;

[0148] R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl, C₁₋₆alkyl,carbocyclyl, heterocyclyl orcarbocyclyl-(C₁₋₆alkylene)_(p)-R²⁷—(C₁₋₆alkylene)_(q)-; wherein R¹⁴ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R³⁰; orR¹⁴ is a group of formula (IC) (as depicted above) wherein:

[0149] R¹⁵ is hydrogen;

[0150] R¹⁶ is C₁₋₆alkyl; wherein R¹⁶ may be optionally substituted oncarbon by one or more groups selected from R³¹;

[0151] n is 1;

[0152] R²⁵, R²⁹ or R³¹ are independently selected from halo, hydroxy,amino, sulphamoyl, C₁₋₆alkoxy, N,N,N—(C₁₋₆alkyl)₃ammonio,N,N—(C₁₋₆alkyl)₂sulphamoylamino, C₁₋₆alkoxycarbonylamino, carbocyclyl,heterocyclyl, carbocyclyl-(C₁₋₆alkylene)_(p)-R³²—(C₁₋₆alkylene)_(q)- orheterocyclyl-(C₁₋₆alkylene)_(r)-R³³—(C₁₋₆alkylene)_(s)-; wherein R²⁵,R²⁹ or R³¹ may be independently optionally substituted on carbon by oneor more R³⁴; and wherein if said heterocyclyl contains an —NH— group,that nitrogen may be optionally substituted by a group selected fromR³⁵;

[0153] R²⁷, R³² or R³³ are independently selected from —O—,—NR³⁶C(O)NR³⁶—, —OC(O)N═C— or —NR³⁶C(O)—; wherein R²³ is hydrogen;

[0154] p, q, r and s are independently selected from 0 or 1;

[0155] R³⁴ is selected from hydroxy, amino, carbamoyl, sulphamoyl ormethoxy;

[0156] R³⁰ or R³⁵ are independently selected from C₁₋₆alkyl orC₁₋₆alkoxycarbonyl.

[0157] R⁵ is a group of formula (IA) as depicted above wherein:

[0158] X is —O—;

[0159] R⁷ is hydrogen;

[0160] R⁸ is hydrogen;

[0161] R⁹ is hydrogen;

[0162] Ring A is phenyl; wherein Ring A is optionally substituted oncarbon by one or more substituents selected from R¹⁸;

[0163] R¹⁰ is carbamoyl or a group of formula (IB) (as depicted above)wherein:

[0164] R¹¹ is hydrogen or C₁₋₆alkyl;

[0165] R¹² and R¹³ are independently selected from hydrogen, carbamoylor C₁₋₆alkyl; wherein R¹² and R¹³ may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵;

[0166] R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl, C₁₋₆alkyl,carbocyclyl, heterocyclyl orcarbocyclyl-(C₁₋₆alkylene)_(p)-R²⁷—(C₁₋₆alkylene)_(q)-; wherein R¹⁴ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R³⁰; orR¹⁴ is a group of formula (IC) (as depicted above) wherein:

[0167] R¹⁵ is hydrogen;

[0168] R¹⁶ is C₁₋₆alkyl; wherein R¹⁶ may be optionally substituted oncarbon by one or more groups selected from R³¹;

[0169] R¹⁸ is hydroxy;

[0170] n is 1;

[0171] R²⁵, R²⁹ or R³¹ are independently selected from halo, hydroxy,amino, sulphamoyl, amidino, C₁₋₆alkoxy, N,N,N—(C₁₋₆alkyl)₃ammonio,N,N—(C₁₋₆alkyl)₂sulphamoylamino, C₁₋₆alkoxycarbonylamino, carbocyclyl,heterocyclyl, carbocyclyl-(C₁₋₆alkylene)_(p)-R³²—(C₁₋₆alkylene)_(q)- orheterocyclyl-(C₁₋₆alkylene)_(r)-R³³—(C₁₋₆alkylene)_(s)-; wherein R²⁵,R²⁹ or R³¹ may be independently optionally substituted on carbon by oneor more R³⁴; and wherein if said heterocyclyl contains an —NH— group,that nitrogen may be optionally substituted by a group selected fromR³⁵;

[0172] R²⁷, R³² or R³³ are independently selected from —O—,—NR³⁶C(O)NR³⁶—, —OC(O)N═C— or —NR³⁶C(O)—; wherein R²³ is hydrogen;

[0173] p, q, r and s are independently selected from 0 or 1;

[0174] R³⁴ is selected from hydroxy, amino, carbamoyl, sulphamoyl ormethoxy;

[0175] R³⁰ or R³⁵ are independently selected from C₁₋₆alkyl orC₁₋₆alkoxycarbonyl.

[0176] R⁵ is a group of formula (IA) as depicted above wherein:

[0177] X is —O—;

[0178] R⁷ is hydrogen;

[0179] R⁸ is hydrogen;

[0180] R⁹ is hydrogen;

[0181] R¹⁰ is carbamoyl or a group of formula (IB) (as depicted above)wherein:

[0182] R¹¹ is hydrogen;

[0183] R¹² and R¹³ are independently selected from hydrogen, carbamoylor methyl; wherein R¹² and R¹³ may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵;

[0184] R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl, methyl,ethyl, propyl, phenyl, 1,5-benzodioxepinyl, 2,3-dihydrobenzofuranyl,piperidinyl, anilinocarbonyl or anilinocarbonyl; wherein R¹⁴ may beoptionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein said piperidinyl may be optionally substituted onnitrogen by a group selected from R³⁰; or R¹⁴ is a group of formula (IC)(as depicted above) wherein:

[0185] R¹⁵ is hydrogen;

[0186] R¹⁶ is methyl, ethyl or hexyl; wherein R¹⁶ may be optionallysubstituted on carbon by one or more groups selected from R³¹;

[0187] n is 1;

[0188] R²⁵, R²⁹ or R³¹ are independently selected from fluoro, hydroxy,amino, sulphamoyl, methoxy, N,N,N-trimethylamino,N,N-dimethylsulphamoylamino, t-butoxycarbonylamino, phenyl, morpholino,imidazolyl, indolyl, 2,4-thiazolidinedionyl, piperazinyl,2-imidazolidinonyl, phenoxy, benxyloxycarbonyliminomethyl,N′-pyridinylureido or N′-pyrimidinylureido; wherein R²⁵, R²⁹ or R³¹ maybe independently optionally substituted on carbon by one or more R³⁴;and wherein said imidazolyl, indolyl, piperazinyl or 2-imidazolidinonylmay be optionally substituted on nitrogen by a group selected from R³⁵;

[0189] R²⁷, R³² or R³³ are independently selected from —O—, —NHC(O)NH—,—OC(O)N═C— or —NHC(O)—;

[0190] p, q, r and s are independently selected from 0 or 1;

[0191] R³⁴ is selected from hydroxy, amino, carbamoyl, sulphamoyl ormethoxy;

[0192] R³⁰ or R³⁵ are independently selected from methyl orC₁₋₆alkoxycarbonyl.

[0193] R⁵ is a group of formula (IA) as depicted above wherein:

[0194] X is —O—;

[0195] R⁷ is hydrogen;

[0196] R⁸ is hydrogen;

[0197] R⁹ is hydrogen;

[0198] Ring A is phenyl; wherein Ring A is optionally substituted oncarbon by one or more substituents selected from R¹⁸;

[0199] R¹⁰ is carbamoyl or a group of formula (IB) (as depicted above)wherein:

[0200] R¹¹ is hydrogen or methyl;

[0201] R¹² and R¹³ are independently selected from hydrogen, carbamoylor methyl; wherein R¹² and R¹³ may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵;

[0202] R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl, methyl,ethyl, propyl, phenyl, 1,5-benzodioxepinyl, 2,3-dihydrobenzofuranyl,piperidinyl, anilinocarbonyl or anilinocarbonyl; wherein R¹⁴ may beoptionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein said piperidinyl may be optionally substituted onnitrogen by a group selected from R³⁰; or R¹⁴ is a group of formula (IC)(as depicted above) wherein:

[0203] R¹⁵ is hydrogen;

[0204] R¹⁶ is methyl, ethyl or hexyl; wherein R¹⁶ may be optionallysubstituted on carbon by one or more groups selected from R³¹;

[0205] n is 1;

[0206] R¹⁸ is hydroxy;

[0207] R²⁵, R²⁹ or R³¹ are independently selected from fluoro, hydroxy,amino, sulphamoyl, amidino, methoxy, N,N,N-trimethylamino,N,N-dimethylsulphamoylamino, t-butoxycarbonylamino, phenyl, morpholino,imidazolyl, indolyl, 2,4-thiazolidinedionyl, piperazinyl,2-imidazolidinonyl, phenoxy, benxyloxycarbonyliminomethyl,N′-pyridinylureido or N′-pyrimidinylureido; wherein R²⁵, R²⁹ or R³¹ maybe independently optionally substituted on carbon by one or more R³⁴;and wherein said imidazolyl, indolyl, piperazinyl or 2-imidazolidinonylmay be optionally substituted on nitrogen by a group selected from R³⁵;

[0208] R²⁷, R³² or R³³ are independently selected from —O—, —NHC(O)NH—,—OC(O)N═C— or —NHC(O)—;

[0209] p, q, r and s are independently selected from 0 or 1;

[0210] R³⁴ is selected from hydroxy, amino, carbamoyl, sulphamoyl ormethoxy;

[0211] R³⁰ or R³⁵ are independently selected from methyl orC₁₋₆alkoxycarbonyl.

[0212] R⁵ is selected from:

[0213] N-{(R)-α-[N′-(2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0214]N-{(R)-α-[N′-(2-trimethylaminoethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0215] N-{(R)-α-[N′-(2-aminoethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0216] N-{(R)-α-[N′-(carbamoylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0217]N-{(R)-α-[N′-((S)-1-carbamoyl-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0218] N-((R)-α-carbamoylbenzyl)carbamoylmethoxy,

[0219]N-{(R)-α-[N′-(1,1-di-hydroxymethyl-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0220]N-{(R)-α-[N′-(hydroxycarbamoylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0221]N-((R)-α-{N′-[N-(2,2,2-trifluoroethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0222]N-((R)-α-{N′-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0223]N-((R)-α-{N′-[N-(2-fluoroethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0224]N-((R)-α-{N′-[N-(ethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0225]N-((R)-α-{N′-[N-(4-hydroxy-3-methoxybenzyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0226]N-((R)-α-{N′-[N-(2-methoxyethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0227]N-((R)-α-{N′-[N-(4-sulphamoylphenethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy,

[0228]N-((R)-α-{N′-[N-(2-N,N-dimethylaminosulphamoylethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoytmethoxy;

[0229]N-[(R)-α-(N′-(N-[2-(N′-pyrimidin-2-ylureido)ethyl]carbamoylmethyl}carbamoyl)benzyl]carbamoylmethoxy;

[0230](N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy;

[0231]N-{(R)-α-[N′-(3-morpholinopropyl)carbamoyl]benzyl}carbamoylmethoxy;

[0232]N-{(R)-α-[N′-(2-imidazol-4-ylethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0233]N-{(R)-α-[N′-(2-N,N-dimethylaminosulphamoylethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0234]N-((R)-α-{N′-[2-(2-hydroxyphenoxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0235]N-{(R)-α-[N′-(3-hydroxy-1,5-benzodioxepin-3-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0236]N-{(R)-α-[N′-(3-t-butoxycarbonylaminobenzyl)carbamoyl]benzyl}carbamoylmethoxy;

[0237]N-((R)-α-{N′-[3-(benxyloxycarbonylimino-1-aminomethyl)benzyl]carbamoyl}benzyl)carbamoylmethoxy;

[0238]N-((R)-α-{N′-[2-(3,4-dihydroxyphenyl)-2-methoxyethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0239]N-{(R)-α-[N′-(2,3-dihydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy;

[0240]N-((R)-α-{N′-[2-(5-methoxyindol-3-yl)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0241]N-((R)-α-{N′-[2-(2,5-dioxothiazolidin-1-yl)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0242]N-((R)-α-{N′-[3-(4-methylpiperazin-1-yl)propyl]carbamoyl}benzyl)carbamoylmethoxy;

[0243]N-{(R)-α-[N′-(4-sulphamoylphenethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0244]N-{(R)-α-[N′-(5,6-dimethoxy-2,3-dihydrobenzofuran-2-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0245]N-{(R)-α-[N′-(1-t-butoxycarbonylpiperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0246]N-{(R)-α-[N′-(4-nitroanilinocarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0247]N-((R)-α-{N′-[2-(N′-pyrimidin-2-ylureido)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0248]N-((R)-α-{N′-[2-(N′-pyridin-2-ylureido)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0249]N-((R)-α-{N′-[2-(4-carbamoylphenoxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0250]N-(R)-α-{N′-[2-(2-oxoimidazolidin-1-yl)ethyl]carbamoyl}benzyl)carbamoylmethoxy;and

[0251] N-{(R)-α-[N′-(3-aminobenzyl)carbamoyl]benzyl}carbamoylmethoxy.

[0252] R⁵ is selected from:

[0253] N-{(R)-α-[N′-(2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0254]N-{(R)-α-[N′-(2-trimethylaminoethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0255] N-{(R)-α-[N′-(2-aminoethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0256] N-{(R)-α-[N′-(carbamoylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0257]N-{(R)-α-[N′-((S)-1-carbamoyl-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy,

[0258] N-((R)-α-carbamoylbenzyl)carbamoylmethoxy;

[0259]N-{(R)-α-[N′-(1,1-di-hydroxymethyl-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0260]N-{(R)-α-[N′-(hydroxycarbamoylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0261]N-((R)-α-{N′-[N-(2,2,2-trifluoroethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0262]N-((R)-α-{N′-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy,

[0263]N-((R)-α-{N′-[N-(2-fluoroethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0264]N-((R)-α-{N′-[N-(ethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0265]N-((R)-α-{N′-[N-(4-hydroxy-3-methoxybenzyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0266] N-((R)-α-{N′-[N-(2-methoxyethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0267]N-((R)-α-{N′-[N-(4-sulphamoylphenethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0268]N-((R)-α-{N′-[N-(2-N,N-dimethylaminosulphamoylethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0269]N-[(R)-α-(N′-(N-[2-(N′-pyrimidin-2-ylureido)ethyl]carbamoylmethyl}carbamoyl)benzyl]carbamoylmethoxy;

[0270](N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy;

[0271]N-{(R)-α-[N′-(3-morpholinopropyl)carbamoyl]benzyl}carbamoylmethoxy;

[0272]N-{(R)-α-[N′-(2-imidazol-4-ylethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0273]N-{(R)-α-[N′-(2-N,N-dimethylaminosulphamoylethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0274]N-((R)-α-{N′-[2-(2-hydroxyphenoxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0275]N-{(R)-α-[N′-(3-hydroxy-1,5-benzodioxepin-3-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0276]N-{(R)-α-[N′-(3-t-butoxycarbonylaminobenzyl)carbamoyl]benzyl}carbamoylmethoxy;

[0277]N-((R)-α-{N′-[4-(N²-benzyloxycarbonylamidino)benzyl]carbamoyl}benzyl)carbamoylmethoxy;

[0278]N-((R)-α-{N′-[2-(3,4-dihydroxyphenyl)-2-methoxyethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0279]N-{(R)-α-[N′-(2,3-dihydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy;

[0280]N-((R)-α-{N′-[2-(5-methoxyindol-3-yl)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0281]N-((R)-α-{N′-[2-(2,5-dioxothiazolidin-1-yl)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0282]N-((R)-α-{N′-[3-(4-methylpiperazin-1-yl)propyl]carbamoyl}benzyl)carbamoylmethoxy;

[0283]N-{(R)-α-[N′-(4-sulphamoylphenethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0284]N-{(R)-α-[N′-(5,6-dimethoxy-2,3-dihydrobenzofuran-2-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0285]N-{(R)-α-[N′-(1-t-butoxycarbonylpiperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0286]N-{(R)-α-[N′-(4-nitroanilinocarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0287]N-((R)-α-{N′-[2-(N′-pyrimidin-2-ylureido)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0288]N-((R)-α-{N′-[2-(N′-pyridin-2-ylureido)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0289]N-((R)-α-{N′-[2-(4-carbamoylphenoxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0290]N-((R)-α-{N′-[2-(2-oxoimidazolidin-1-yl)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

[0291] N-{(R)-α-[N′-(3-aminobenzyl)carbamoyl]benzyl}carbamoylmethoxy;

[0292]N-{(R)-α-[N′-(piperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

[0293] N-{(R)-α-[N′-(4-amidinobenzyl)carbamoyl]benzyl}carbamoylmethoxy;and

[0294](N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)-N′-methylcarbamoyl]-4-hydroxybenzyl}carbamoylmethoxy.

[0295] Ring A is aryl.

[0296] Ring A is phenyl.

[0297] X is —O—.

[0298] Therefore in another aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

[0299] R¹ and R² are independently selected from C₁₋₄alkyl;

[0300] v is 0;

[0301] R³ and R⁶ are hydrogen;

[0302] R⁴ is methylthio;

[0303] R⁵ is a group of formula (IA) as depicted above wherein:

[0304] X is —O—;

[0305] R⁷ is hydrogen;

[0306] R⁸ is hydrogen;

[0307] R⁹ is hydrogen;

[0308] Ring A is aryl;

[0309] R¹⁰ is carbamoyl or N—(C₁₋₁₀alkyl)carbamoyl or a group of formula(IB) (as depicted above) wherein R¹⁰ is optionally substituted on carbonby one or more substituents selected from R²³ and wherein:

[0310] R¹¹ is hydrogen;

[0311] R¹² and R¹³ are independently selected from hydrogen, carbamoylor C₁₋₆alkyl; wherein R¹² and R¹³ may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵;

[0312] R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl, C₁₋₆alkyl,carbocyclyl, heterocyclyl orcarbocyclyl-(C₁₋₆alkylene)_(p)-R²⁷—(C₁₋₆alkylene)_(q)-; wherein R¹⁴ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R³⁰; orR¹⁴ is a group of formula (IC) (as depicted above) wherein:

[0313] R¹⁵ is hydrogen;

[0314] R¹⁶ is C₁₋₆alkyl; wherein R¹⁶ may be optionally substituted oncarbon by one or more groups selected from R³¹;

[0315] n is 1;

[0316] R²³ is hydroxy;

[0317] R²⁵, R²⁹ or R³¹ are independently selected from halo, hydroxy,amino, sulphamoyl, C₁₋₆alkoxy, N,N,N—(C₁₋₆alkyl)₃ammonio,N,N—(C₁₋₆alkyl)₂sulphamoylamino, C₁₋₆alkoxycarbonylamino, carbocyclyl,heterocyclyl, carbocyclyl-(C₁₋₆alkylene)_(p)-R³²—(C₁₋₆alkylene)_(q)- orheterocyclyl-(C₁₋₆alkylene)_(r)-R³³—(C₁₋₆alkylene)_(s)-; wherein R²⁵,R²⁹ or R³¹ may be independently optionally substituted on carbon by oneor more R³⁴; and wherein if said heterocyclyl contains an —NH— group,that nitrogen may be optionally substituted by a group selected fromR³⁵;

[0318] R²⁷, R³² or R³³ are independently selected from —O—,—NR³⁶C(O)NR³⁶—, —OC(O)N═C— or —NR³⁶C(O)—; wherein R²³ is hydrogen;

[0319] p, q, r and s are independently selected from 0 or 1;

[0320] R³⁴ is selected from hydroxy, amino, carbamoyl, sulphamoyl ormethoxy;

[0321] R³⁰ or R³⁵ are independently selected from C₁₋₆alkyl orC₁₋₆alkoxycarbonyl; or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

[0322] Therefore in another aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

[0323] R^(v) and R^(w) are both hydrogen;

[0324] One of R¹ and R² is ethyl and the other is butyl or R¹ and R² areboth butyl;

[0325] R^(x) and R^(y) are both hydrogen;

[0326] v is 0;

[0327] R³ and R⁶ are hydrogen;

[0328] R⁴ is hydrogen or methylthio;

[0329] R⁵ is a group of formula (IA) as depicted above wherein:

[0330] X is —O—;

[0331] R⁷ is hydrogen;

[0332] R⁸ is hydrogen;

[0333] R⁹ is hydrogen;

[0334] Ring A is aryl; wherein Ring A is optionally substituted oncarbon by one or more substituents selected from R¹⁸;

[0335] R¹⁰ is carbamoyl or N-C₁₋₁₀alkyl)carbamoyl or a group of formula(IB) (as depicted above) wherein R¹⁰ is optionally substituted on carbonby one or more substituents selected from R²³ and wherein:

[0336] R¹¹ is hydrogen or C₁₋₆alkyl;

[0337] R¹² and R¹³ are independently selected from hydrogen, carbamoylor C₁₋₆alkyl; wherein R¹² and R¹³ may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵;

[0338] R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl, C₁₋₆alkyl,carbocyclyl, heterocyclyl orcarbocyclyl-(C₁₋₆alkylene)_(p)-R²⁷—(C₁₋₆alkylene)_(q)-; wherein R¹⁴ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R³⁰; orR¹⁴ is a group of formula (IC) (as depicted above) wherein:

[0339] R¹⁵ is hydrogen;

[0340] R¹⁶ is C₁₋₆alkyl; wherein R¹⁶ may be optionally substituted oncarbon by one or more groups selected from R³¹;

[0341] n is 1;

[0342] R¹⁸ is hydroxy;

[0343] R²³ is hydroxy;

[0344] R²⁵, R²⁹ or R³¹ are independently selected from halo, hydroxy,amino, sulphamoyl, amidino, C₁₋₆alkoxy, N,N,N—(C₁₋₆alkyl)₃ammonio,N,N—(C₁₋₆alkyl)₂sulphamoylamino, C₁₋₆alkoxycarbonylamino, carbocyclyl,heterocyclyl, carbocyclyl-(C₁₋₆alkylene)_(p)-R³²—(C₁₋₆alkylene)_(q)- orheterocyclyl-(C₁₋₆alkylene)_(r)-R³³—(C₁₋₆alkylene)_(s)-; wherein R²⁵,R²⁹ or R³¹ may be independently optionally substituted on carbon by oneor more R³⁴; and wherein if said heterocyclyl contains an —NH— group,that nitrogen may be optionally substituted by a group selected fromR³⁵;

[0345] R²⁷, R³² or R³³ are independently selected from —O—,—NR³⁶C(O)NR³⁶—, —OC(O)N═C— or —NR³⁶C(O)—; wherein R²³ is hydrogen;

[0346] p, q, r and s are independently selected from 0 or 1;

[0347] R³⁴ is selected from hydroxy, amino, carbamoyl, sulphamoyl ormethoxy;

[0348] R³⁰ or R³⁵ are independently selected from C₁₋₆alkyl orC₁₋₆alkoxycarbonyl. or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

[0349] In another aspect of the invention, preferred compounds of theinvention are any one of the examples or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

[0350] In a further aspect of the invention, preferred compounds of theinvention are Examples 3, 5, 8, 18, 19, 22, 27, 28, 34, 36, 37 or 41 ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

[0351] Preferred aspects of the invention are those which relate to thecompound of formula (I) or a pharmaceutically acceptable salt thereof.

[0352] Another aspect of the present invention provides a process forpreparing a compound of formula (I) or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof which process(wherein variable groups are, unless otherwise specified, as defined informula (I)) comprises of:

[0353] Process 1): oxidising a benzothiazepine of formula (II):

[0354] Process 2): for compounds of formula (I) wherein X is —O—,—NR^(a)or —S—; reacting a compound of formula (IIIa) or (IIIb):

[0355] with a compound of formula (IV):

[0356] wherein L is a displaceable group;

[0357] Process 3): reacting an acid of formula (Va) or (Vb):

[0358] or an activated derivative thereof; with an amine of formula(VI):

[0359] Process 4): for compounds of formula (I) wherein R¹⁰ is a groupof formula (IB); reacting a compound of formula (I) wherein R¹⁰ iscarboxy with an amine of formula (VII):

[0360] Process 5): for compounds of formula (I) wherein R¹⁰ is a groupof formula (IB) and R¹⁴ is a group of formula (IC) reacting a compoundof formula (I) wherein R¹⁴ is carboxy with an amine of formula (VIII):

R¹⁵R¹⁶NH  (VIII)

[0361] Process 6) for compounds of formula (I) wherein one of R⁴ and R⁵are independently selected from C₁₋₆alkylthio optionally substituted oncarbon by one or more R¹⁷; reacting a compound of formula (IXa) or(IXb):

[0362] wherein L is a displaceable group; with a thiol of formula (X):

R^(y)—H  (X)

[0363] wherein R^(y) is C₁₋₆alkylthio optionally substituted on carbonby one or more R¹⁶;

[0364] and thereafter if necessary or desirable:

[0365] i) converting a compound of the formula (I) into another compoundof the formula (I);

[0366] ii) removing any protecting groups;

[0367] iii) forming a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug.

[0368] L is a displaceable group, suitable values for L are for example,a halogeno or sulphonyloxy group, for example a chloro, bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group.

[0369] R^(x) is C₁₋₆alkyl. Preferably R^(x) is methyl or ethyl. Morepreferably R^(x) is methyl.

[0370] Specific reaction conditions for the above reactions are asfollows.

[0371] Process 1): Benzothiazepines of formula (II) may be oxidisedunder standard sulphur oxidation conditions; for example using hydrogenperoxide and trifluoroacetic acid at a temperature in the range of 0° C.to reflux, preferably at or near room temperature.

[0372] Compounds of formula (II) may be prepared according to Scheme Ifor compounds of formula (I) wherein R^(x) and R^(y) are hydrogen. Theskilled person will appreciate that where R^(x) and R^(y) are not bothhydrogen the following synthetic route needs to be manipulated usingprocedures known to the skilled person:

[0373] wherein L is a displaceable group as defined above, and Y is adisplaceable group, for example halo.

[0374] Compounds of formula (IIa) and (IIc) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

[0375] Process 2): Compounds of formula (IIIa) or (IIIb) may be reactedwith compounds of formula (IV) in the presence of a base for example aninorganic base such as sodium carbonate, or an organic base such asHunigs base, in the presence of a suitable solvent such as acetonitrile,dichloromethane or tetrahydrofuran at a temperature in the range of 0°C. to reflux, preferably at or near reflux.

[0376] Compounds of formula (IIIa) or (IIIb) may be prepared in asimilar manner to compounds of formula (II) (but wherein R⁴ or R⁵ is—OH, —NH(R^(a)) or —SH followed by the oxidation step of Process 1).

[0377] Compounds of formula (IV) are commercially available compounds,or they are known in the literature, or they are prepared by standardprocesses known in the art.

[0378] Process 3) and Process 4) and Process 5): Acids and amines may becoupled together in the presence of a suitable coupling reagent.Standard peptide coupling reagents known in the art can be employed assuitable coupling reagents, or for example carbonyldiimidazole anddicyclohexyl-carbodiimide, optionally in the presence of a catalyst suchas dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in thepresence of a base for example triethylamine, pyridine, or2,6-di-alkyl-pyridines such as 2,6-lutidine or2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide,dichloromethane, benzene, tetrahydrofuran and dimethylformamide. Thecoupling reaction may conveniently be performed at a temperature in therange of −40 to 40° C.

[0379] Suitable activated acid derivatives include acid halides, forexample acid chlorides, and active esters, for example pentafluorophenylesters. The reaction of these types of compounds with amines is wellknown in the art, for example they may be reacted in the presence of abase, such as those described above, and in a suitable solvent, such asthose described above. The reaction may conveniently be performed at atemperature in the range of −40 to 40° C.

[0380] Compounds of formula (Va) or (Vb) wherein X=—O—,—NR^(a)—,—S— maybe prepared according to Scheme 2:

[0381] wherein L is a displaceable group as defined above.

[0382] Compounds of formula (Va) and (Vb) where X is —SO— or —SO₂— maybe prepared by oxidising the resulting compounds of formula (Va) and(Vb) from Scheme 2 where X is —S—.

[0383] Compounds of formula (Va) or (Vb) wherein X is —CH₂— may beprepared according to Scheme 3.

[0384] Compounds of formula (Vc), (VI), (VII) and (VIII) arecommercially available compounds, or they are known in the literature,or they are prepared by standard processes known in the art.

[0385] Process 6): Compounds of formula (IXa) and (IXb) may be reactedwith thiols of formula (X) in the presence of base, for example aninorganic base such as sodium carbonate or an organic base such asHunigs base, in the presence of a suitable solvent such as DMF or THF ata temperature in the range of 0° C. to reflux.

[0386] Compounds of formula (IXa) and (IXb) may be prepared by any ofthe procedures above for the preparation of compounds of formula (I),but wherein one of R⁴ and R⁵ is L.

[0387] Compounds of formula (X) are commercially available compounds, orthey are known in the literature, or they are prepared by standardprocesses known in the art.

[0388] It will be appreciated that certain of the various ringsubstituents in the compounds of the present invention may be introducedby standard aromatic substitution reactions or generated by conventionalfunctional group modifications either prior to or immediately followingthe processes mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

[0389] It will also be appreciated that in some of the reactionsmentioned herein it may be necessary/desirable to protect any sensitivegroups in the compounds. The instances where protection is necessary ordesirable and suitable methods for protection are known to those skilledin the art. Conventional protecting groups may be used in accordancewith standard practice (for illustration see T. W. Green, ProtectiveGroups in Organic Synthesis, John Wiley and Sons, 1999). Thus, ifreactants include groups such as amino, carboxy or hydroxy it may bedesirable to protect the group in some of the reactions mentionedherein.

[0390] A suitable protecting group for an amino or alkylamino group is,for example, an acyl group, for example an alkanoyl group such asacetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group,for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.The deprotection conditions for the above protecting groups necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or alkoxycarbonyl group or an aroyl group maybe removed for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

[0391] A suitable protecting group for a hydroxy group is, for example,an acyl group, for example an alkanoyl group such as acetyl, an aroylgroup, for example benzoyl, or an arylmethyl group, for example benzyl.The deprotection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

[0392] A suitable protecting group for a carboxy group is, for example,an esterifying group, for example a methyl or an ethyl group which maybe removed, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

[0393] The protecting groups may be removed at any convenient stage inthe synthesis using conventional techniques well known in the chemicalart.

[0394] As stated hereinbefore the compounds defined in the presentinvention possess IBAT inhibitory activity. These properties may beassessed, for example, using an in vitro test assay for studying theeffect on bile acid uptake in IBAT-transfected cells (Smith L.,Price-Jones M. J., Hugnes K. T. and Jones N. R. A.; J BiomolecularScreening, 3, 227-230) or in vivo by studying the effect onradiolabelled bile acid absorption in mice/rats (Lewis M. C., BrieaddyL. E. and Root C., J., J Lip Res 1995, 36, 1098-1105).

[0395] According to a further aspect of the invention there is provideda pharmaceutical composition which comprises a compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

[0396] The composition may be in a form suitable for oraladministration, for example as a tablet or capsule, for parenteralinjection (including intravenous, subcutaneous, intramuscular,intravascular or infusion) as a sterile solution, suspension oremulsion, for topical administration as an ointment or cream or forrectal administration as a suppository.

[0397] In general the above compositions may be prepared in aconventional manner using conventional excipients.

[0398] The compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, willnormally be administered to a warm-blooded animal at a unit dose withinthe range 5-5000 mg per square meter body area of the animal, i.e.approximately 0.1-100 mg/kg, preferably 0.02-50 mg/kg, and this normallyprovides a therapeutically-effective dose. A unit dose form such as atablet or capsule will usually contain, for example 1-250 mg of activeingredient. Preferably a daily dose in the range of 1-50 mg/kg,particularly 0.1-10 mg/kg is employed. However the daily dose willnecessarily be varied depending upon the host treated, the particularroute of administration, and the severity of the illness being treated.Accordingly the optimum dosage may be determined by the practitioner whois treating any particular patient.

[0399] According to a further aspect of the present invention there isprovided a compound of the formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use in a method of prophylactic or therapeutictreatment of a warm-blooded animal, such as man.

[0400] We have found that the compounds defined in the presentinvention, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, are effective IBAT inhibitors, andaccordingly have value in the treatment of disease states associatedwith hyperlipidaemic conditions.

[0401] Thus according to this aspect of the invention there is provideda compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use as a medicament.

[0402] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,as defined hereinbefore, in the production of an IBAT inhibitory effectin a warm-blooded animal, such as man.

[0403] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,as defined hereinbefore, in the treatment of hyperlipidaemic conditionsin a warm-blooded animal, such as man.

[0404] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,as defined hereinbefore in the manufacture of a medicament for use inthe production of an IBAT inhibitory effect in a warm-blooded animal,such as man.

[0405] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,as defined hereinbefore in the manufacture of a medicament for use inthe treatment of hyperlipidaemic conditions in a warm-blooded animal,such as man.

[0406] Herein, where “the production of an IBAT inhibitory effect” or“producing an IBAT inhibitory effect” is referred to particularly thisrefers to the treatment of hyperlipidaemic conditions. In anotheraspect, “the production of an IBAT inhibitory effect” or “producing anIBAT inhibitory effect”refers to the treatment of dyslipidemicconditions and disorders such as hyperlipidaemia, hypertrigliceridemia,hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (highVLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia,hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In anotheraspect “the production of an IBAT inhibitory effect” or “producing anIBAT inhibitory effect” refers to the treatment of different clinicalconditions such as atherosclerosis, arteriosclerosis, arrhythmia,hyper-thrombotic conditions, vascular dysfunction, endothelialdysfunction, heart failure, coronary heart diseases, cardiovasculardiseases, myocardial infarction, angina pectoris, peripheral vasculardiseases, inflammation of cardiovascular tissues such as heart, valves,vasculature, arteries and veins, aneurisms, stenosis, restenosis,vascular plaques, vascular fatty streaks, leukocytes, monocytes and/ormacrophage infiltration, intimal thickening, medial thinning, infectiousand surgical trauma and vascular thrombosis, stroke and transientischaemic attacks. In another aspect “the production of an IBATinhibitory effect” or “producing an IBAT inhibitory effect” refers tothe treatment of atherosclerosis, coronary heart diseases, myocardialinfarction, angina pectoris, peripheral vascular diseases, stroke andtransient ischaemic attacks in a warm-blooded animal, such as man.

[0407] According to a further feature of this aspect of the inventionthere is provided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

[0408] According to a further feature of this aspect of the inventionthere is provided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

[0409] The size of the dose required for the therapeutic or prophylactictreatment will necessarily be varied depending on the host treated, theroute of administration and the severity of the illness being treated. Aunit dose in the range, for example, 0.1-50 mg/kg preferably 0.1-10mg/kg is envisaged.

[0410] The IBAT inhibitory activity defined hereinbefore may be appliedas a sole therapy or may involve, in addition to a compound of theinvention, one or more other substances and/or treatments. Such conjointtreatment may be achieved by way of the simultaneous, sequential orseparate administration of the individual components of the treatment.According to this aspect of the invention there is provided apharmaceutical product comprising a compound of the formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore and an additional IBATinhibitory substance as defined hereinbefore and an additionalhypolipidaemic agent for the conjoint treatment of hyperlipidaemia.

[0411] In another aspect of the invention, the compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, may be administered in association with an HMGCo-A reductase inhibitor, or pharmaceutically acceptable salts,solvates, solvates of such salts or prodrugs thereof. Suitable HMG Co-Areductase inhibitors, pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof are statins well known in theart. Particular statins are fluvastatin, lovastatin, pravastatin,simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin,mevastatin and(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid (rosuvastatin), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof. A particular statin isatorvastatin, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof. A more particular statin isatorvastatin calcium salt. A further particular statin is(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid, or a pharmaceutically acceptable salt, solvate, solvate of such asalt or a prodrug thereof. A more particular statin is rosuvastatincalcium salt.

[0412] In an additional aspect of the invention, the compound of formula(I), or a pharmaceutically acceptable salt, solvate, solvate of such asalt or a prodrug thereof may be administered in association with an HMGCo-A reductase inhibitor, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and/or a bile acidbinder thereby avoiding a possible risk of excess of bile acids in coloncaused by the inhibition of the ileal bile acid transport system. Anexcess of bile acids in the visceral contents may cause diarrhoea. Thus,the present invention also provides a treatment of a possible sideeffect such as diarrhoea in patients during therapy comprising thecompound of formula (I), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

[0413] An HMG CoA-reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof will by itsaction decrease the endogenous cholesterol available for the bile acidsynthesis and have an additive effect in combination with the compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof on lipid lowering.

[0414] Suitable bile acid binders for such a combination therapy areresins, such as cholestyramine and cholestipol. One advantage is thatthe dose of bile acid binder might be kept lower than the therapeuticdose for treatment of cholesterolaemia in single treatment comprisingsolely a bile acid binder. By a low dose of bile acid binder anypossible side effects caused by poor tolerance of the patient to thetherapeutic dose could also be avoided.

[0415] Therefore in an additional feature of the invention, there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof in simultaneous, sequential orseparate administration with an effective amount of an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

[0416] Therefore in an additional feature of the invention, there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof in simultaneous, sequential orseparate administration with a bile acid binder.

[0417] Therefore in an additional feature of the invention, there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof in simultaneous, sequential orseparate administration with an effective amount of an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in simultaneous, sequentialor separate administration with a bile acid binder.

[0418] Therefore in an additional feature of the invention, there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof in simultaneous, sequential orseparate administration with an effective amount of an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

[0419] Therefore in an additional feature of the invention, there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof in simultaneous, sequential orseparate administration with an effective amount of a bile acid binder.

[0420] Therefore in an additional feature of the invention, there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof in simultaneous, sequential orseparate administration with an effective amount of an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in simultaneous, sequentialor separate administration with a bile acid binder.

[0421] According to a further aspect of the invention there is provideda pharmaceutical composition which comprises a compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

[0422] According to a further aspect of the invention there is provideda pharmaceutical composition which comprises a compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, and a bile acid binder, in association with apharmaceutically acceptable diluent or carrier.

[0423] According to a further aspect of the invention there is provideda pharmaceutical composition which comprises a compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid binder in association with apharmaceutically acceptable diluent or carrier.

[0424] According to a further aspect of the present invention there isprovided a kit comprising a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

[0425] According to a further aspect of the present invention there isprovided a kit comprising a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid binder.

[0426] According to a further aspect of the present invention there isprovided a kit comprising a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof and a bile acid binder.

[0427] According to a further aspect of the present invention there isprovided a kit comprising:

[0428] a) a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in a firstunit dosage form;

[0429] b) an HMG Co-A reductase inhibitor, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof;in a second unit dosage form; and

[0430] c) container means for containing said first and second dosageforms.

[0431] According to a further aspect of the present invention there isprovided a kit comprising:

[0432] a) a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in a firstunit dosage form;

[0433] b) a bile acid binder; in a second unit dosage form; and

[0434] c) container means for containing said first and second dosageforms.

[0435] According to a further aspect of the present invention there isprovided a kit comprising:

[0436] a) a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in a firstunit dosage form;

[0437] b) an HMG Co-A reductase inhibitor, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof;in a second unit dosage form;

[0438] c) a bile acid binder, in a third unit dosage form; and

[0439] d) container means for containing said first, second and thirddosage forms.

[0440] According to a further aspect of the present invention there isprovided a kit comprising:

[0441] a) a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, togetherwith a pharmaceutically acceptable diluent or carrier, in a first unitdosage form;

[0442] b) an HMG Co-A reductase inhibitor, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in a second unit dosage form; and

[0443] c) container means for containing said first and second dosageforms.

[0444] According to a further aspect of the present invention there isprovided a kit comprising:

[0445] a) a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, togetherwith a pharmaceutically acceptable diluent or carrier, in a first unitdosage form;

[0446] b) a bile acid binder, in a second unit dosage form; and

[0447] c) container means for containing said first and second dosageforms.

[0448] According to a further aspect of the present invention there isprovided a kit comprising:

[0449] a) a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, togetherwith a pharmaceutically acceptable diluent or carrier, in a first unitdosage form;

[0450] b) an HMG Co-A reductase inhibitor, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in a second unit dosage form; and

[0451] c) a bile acid binder; in a third unit dosage form; and

[0452] d) container means for containing said first, second and thirddosage forms.

[0453] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in themanufacture of a medicament for use in the production of an IBATinhibitory effect in a warm-blooded animal, such as man.

[0454] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a bile acid binder, in the manufacture of a medicament for use inthe production of an IBAT inhibitory effect in a warm-blooded animal,such as man.

[0455] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, and a bileacid binder, in the manufacture of a medicament for use in theproduction of an IBAT inhibitory effect in a warm-blooded animal, suchas man.

[0456] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in the manufactureof a medicament for use in the treatment of hyperlipidaemic conditionsin a warm-blooded animal, such as man.

[0457] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof, abile acid binder, in the manufacture of a medicament for use in thetreatment of hyperlipidaemic conditions in a warm-blooded animal, suchas man.

[0458] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a bile acidbinder, in the manufacture of a medicament for use in the treatment ofhyperlipidaemic conditions in a warm-blooded animal, such as man.

[0459] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

[0460] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a bile acid binder, optionally together with apharmaceutically acceptable diluent or carrier to a warm-blooded animal,such as man in need of such therapeutic treatment.

[0461] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptableexcipient, with the simultaneous, sequential or separate administrationof an effective amount of a bile acid binder, optionally together with apharmaceutically acceptable diluent or carrier to a warm-blooded animal,such as man in need of such therapeutic treatment.

[0462] According to an additional further aspect of the presentinvention there is provided a combination treatment comprising theadministration of an effective amount of a compound of the formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, optionally together with a pharmaceuticallyacceptable diluent or carrier, with the simultaneous, sequential orseparate administration one or more of the following agents selectedfrom:

[0463] a CETP (cholesteryl ester transfer protein) inhibitor, forexample those referenced and described in WO 00/38725 page 7 line22-page 10, line 17 which are incorporated herein by reference;

[0464] a cholesterol absorption antagonist for example azetidinones suchas SCH 58235 and those described in U.S. Pat. No. 5,767,115 which areincorporated herein by reference;

[0465] a MTP (microsomal transfer protein) inhibitor for example thosedescribed in Science, 282, 751-54, 1998 which are incorporated herein byreference;

[0466] a fibric acid derivative; for example clofibrate, gemfibrozil,fenofibrate, ciprofibrate and bezafibrate;

[0467] a nicotinic acid derivative, for example, nicotinic acid(niacin), acipimox and niceritrol;

[0468] a phytosterol compound for example stanols;

[0469] probucol;

[0470] an anti-obesity compound for example orlistat (EP 129,748) andsibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);

[0471] an antihypertensive compound for example an angiotensinconverting enzyme inhibitor, an angiotensin II receptor antagonist, anandrenergic blocker, an alpha andrenergic blocker, a beta andrenergicblocker, a mixed alpha/beta andrenergic blocker, an andrenergicstimulant, calcium channel blocker, a diuretic or a vasodilator;

[0472] insulin;

[0473] sulphonylureas including glibenclamide, tolbutamide;

[0474] metformin; and/or

[0475] acarbose;

[0476] or a pharmaceutically acceptable salt, solvate, solvate of such asalt or a prodrug thereof, optionally together with a pharmaceuticallyacceptable diluent or carrier to a warm-blooded animal, such as man inneed of such therapeutic treatment.

[0477] Particular ACE inhibitors or pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof, including activemetabolites, which can be used in combination with a compound of formula(I) include but are not limited to, the following compounds: alacepril,alatriopril, altiopril calcium, ancovenin, benazepril, benazeprilhydrochloride, benazeprilat, benzoylcaptopril, captopril,captopril-cysteine, captopril-glutathione, ceranapril, ceranopril,ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid,enalapril, enalaprilat, enapril, epicaptopril, foroxymithine,fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinoprilsodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4,idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril,lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril,muracein A, muracein B, muracein C, pentopril, perindopril,perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride,quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride,spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocaprilhydrochloride, teprotide, trandolapril, trandolaprilat, utibapril,zabicipril, zabiciprilat, zofenopril and zofenoprilat. Preferred ACEinhibitors for use in the present invention are ramipril, ramiprilat,lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors foruses in the present invention are ramipril and ramiprilat.

[0478] Preferred angiotensin II antagonists, pharmaceutically acceptablesalts, solvates, solvate of such salts or a prodrugs thereof for use incombination with a compound of formula (I) include, but are not limitedto, compounds: candesartan, candesartan cilexetil, losartan, valsartan,irbesartan, tasosartan, telmisartan and eprosartan. Particularlypreferred angiotensin II antagonists or pharmaceutically acceptablederivatives thereof for use in the present invention are candesartan andcandesartan cilexetil.

[0479] In another aspect of the invention, the compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, may be administered in association with a PPARalpha and/or gamma agonist, or pharmaceutically acceptable salts,solvates, solvates of such salts or prodrugs thereof. Suitable PPARalpha and/or gamma agonists, pharmaceutically acceptable salts,solvates, solvates of such salts or prodrugs thereof are well known inthe art. These include the compounds described in WO 01/12187, WO01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO01/40170, J Med Chem, 1996, 39, 665, Expert Opinion on TherapeuticPatents, 10 (5), 623-634 (in particular the compounds described in thepatent applications listed on page 634) and J Med Chem, 2000, 43, 527which are all incorporated herein by reference. Particularly a PPARalpha and/or gamma agonist refers to WY-14643, clofibrate, fenofibrate,bezafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone,eglitazone, proglitazone, BRL-49634, KRP-297, JTT-501, SB 213068, GW1929, GW 7845, GW 0207, L-796449, L-165041, NN622/Ragaglitazar, BMS298585and GW 2433. Particularly a PPAR alpha and/or gamma agonist refersto(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoicacid and pharmaceutically acceptable salts thereof.

[0480] Therefore in an additional feature of the invention, there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof in simultaneous, sequential orseparate administration with an effective amount of a PPAR alpha and/orgamma agonist, or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

[0481] Therefore in an additional feature of the invention, there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof in simultaneous, sequential orseparate administration with an effective amount of a PPAR alpha and/orgamma agonist, or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

[0482] According to a further aspect of the invention there is provideda pharmaceutical composition which comprises a compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, and a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

[0483] According to a further aspect of the present invention there isprovided a kit comprising a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

[0484] According to a further aspect of the present invention there isprovided a kit comprising:

[0485] a) a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in a firstunit dosage form;

[0486] b) a PPAR alpha and/or gamma agonist, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in a second unit dosage form; and

[0487] c) container means for containing said first and second dosageforms.

[0488] According to a further aspect of the present invention there isprovided a kit comprising:

[0489] a) a compound of formula (1), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, togetherwith a pharmaceutically acceptable diluent or carrier, in a first unitdosage form;

[0490] b) a PPAR alpha and/or gamma agonist, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in a second unit dosage form; and

[0491] c) container means for containing said first and second dosageforms.

[0492] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in themanufacture of a medicament for use in the production of an IBATinhibitory effect in a warm-blooded animal, such as man.

[0493] According to another feature of the invention there is providedthe use of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof, aPPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in the manufactureof a medicament for use in the treatment of hyperlipidaemic conditionsin a warm-blooded animal, such as man.

[0494] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

[0495] In addition to their use in therapeutic medicine, the compoundsof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof, are also useful as pharmacologicaltools in the development and standardisation of in vitro and in vivotest systems for the evaluation of the effects of inhibitors of IBAT inlaboratory animals such as cats, dogs, rabbits, monkeys, rats and mice,as part of the search for new therapeutic agents.

[0496] Many of the intermediates described herein are novel and are thusprovided as a further feature of the invention.

[0497] In the above other pharmaceutical composition, process, method,use and medicament manufacture features, the alternative and particularembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

[0498] The invention will now be illustrated in the following nonlimiting examples, in which standard techniques known to the skilledchemist and techniques analogous to those described in these examplesmay be used where appropriate, and in which, unless otherwise stated:

[0499] (i) evaporations were carried out by rotary evaporation in vacuoand work up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

[0500] (ii) all reactions were carried out under an inert atmosphere atambient temperature, typically in the range 18-25° C., with solvents ofHPLC grade under anhydrous conditions, unless otherwise stated;

[0501] (iii) column chromatography (by the flash procedure) wasperformed on Silica gel 40-63 μm (Merck);

[0502] (iv) yields are given for illustration only and are notnecessarily the maximum attainable;

[0503] (v) the structures of the end products of the formula (I) weregenerally confirmed by nuclear (generally proton) magnetic resonance(NMR) and mass spectral techniques; magnetic resonance chemical shiftvalues were measured in deuterated CD₃OD (unless otherwise stated) onthe delta scale (ppm downfield from tetramethylsilane); proton data isquoted unless otherwise stated; spectra were recorded on a VarianMercury-300 MHz, Varian Unity plus-400 MHz, Varian Unity plus-600 MHz oron Varian Inova-500 MHz spectrometer; and peak multiplicities are shownas follows: s, singlet; d, doublet; dd, double doublet; t, triplet; tt,triple triplet; q, quartet; tq, triple quartet; m, multiplet; br, broad;LCMS were recorded on a Waters ZMD, LC column xTerra MS C₈(Waters),detection with a HP 1100 MS-detector diode array equipped; mass spectra(MS) (loop) were recorded on VG Platform II (Fisons Instruments) with aHP-1100 MS-detector diode array equipped; unless otherwise stated themass ion quoted is (MH⁺);

[0504] (vi) unless further details are specified in the text, analyticalhigh performance liquid chromatography (HPLC) was performed on Prep LC2000 (Waters), Kromasil C₈, 7 μm, (Akzo Nobel); MeCN and de-ionisedwater 100 mM ammonium acetate as mobile phases, with suitablecomposition;

[0505] (vii) intermediates were not generally fully characterised andpurity was assessed by thin layer chromatography (TLC), HPLC, infra-red(IR), MS or NMR analysis;

[0506] (viii) where solutions were dried sodium sulphate was the dryingagent;

[0507] (ix) where an “ISOLUTE” column is referred to, this means acolumn containing 2 g of silica, the silica being contained in a 6 mldisposable syringe and supported by a porous disc of 54 Å pore size,obtained from International Sorbent Technology under the name “ISOLUTE”;“ISOLUTE” is a registered trade mark;

[0508] (x) the following abbreviations may be used hereinbefore orhereinafter:-

[0509] DCM dichloromethane;

[0510] DMF N,N-dimethylformamide;

[0511] TBTU o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate;

[0512] EtOAc ethyl acetate;

[0513] MeCN acetonitrile;

[0514] TFA trifluoroacetic acid;

[0515] HATU o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate; and

[0516] DIPEA di-isopropylethylamine.

Example 11,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-hydroxethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0517]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1; 50 mg, 0.082 mmol) and 2-aminoethanol (18 μl, 0.3 mmol) weredissolved in DCM (5 ml). The solution was cooled to 0° C. and TBTU (32mg, 0.1 mmol) was added. The mixture was stirred for 15 min at roomtemperature. An additional amount of 2-aminoethanol (100 μl, 1.65 mmol),TBTU (90 mg, 0.28 mmol) and DMF (2 ml) were added. The reaction mixturewas stirred over night at room temperature The solvents were evaporatedunder reduced pressure and the residue was purified by preparative HPLCusing MeCN/ammonium acetate buffer (60:40) as eluent. The collectedfractions were lyophilised to obtain 7 mg (13%) of the title compound.NMR (300 MHz): 0.7-0.9 (m, 6H), 1.0-1.25 (m, 4H), 1.4-1.65 (m, 4H), 2.15(s, 3H), 3.2 (s, 2H), 3.5-8.85 (m, 4H), 4.6-4.8 (m, 2H), 5.5 (s, 1H),6.75 (s, 1H), 6.95-7.5 (m, 11H).

Example 21,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-trimethylaminoethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepineAcetate Salt

[0518]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1; 50 mg, 0.082 mmol), (2-aminoethyl)trimethylammonium chloridehydrochloride (57 mg, 0.33 mmol) and triethylamine were added to DCM (5ml) and DMF (1 ml). TBTU (42 mg, 0.13 mmol) was added and the mixturewas stirred at room temperature for 1 h. The solvents were evaporatedunder reduced pressure and the residue was purified by preparative HPLCusing MeCN/ammonium acetate buffer (65:35) as eluent. The collectedfractions were lyophilised to obtain 8 mg (13%) of the title compound.NMR (300 MHz): 0.7-0.9 (m, 6H), 1.0-1.3 (m, 4H), 1.4-1.65 (m, 4H), 1.95(s, 3H), 2.2 (s, 3H), 3.1 (s, 9H), 3.3 (s, 2H), 3.45-3.5 (m, 2H),3.55-3.8 (m, 4H), 4.75 (s, 1H), 5.4 (s, 1H), 6.75 (s, 1H), 6.95-7.5 (m,11H).

Example 31,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-aminoethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepineAcetic Acid Salt

[0519]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1; 50 mg, 0.082 mmol) and t-butyl N-(2-aminoethyl)carbamate (40mg, 0.25 mmol) were added to DCM (5 ml). TBTU (42 mg, 0.13 mmol) wasadded and the reaction mixture was stirred for 2 hours at roomtemperature. TFA (1 ml) was added and the mixture was stirred for 1 hourat room temperature The solvents were evaporated under reduced pressureand the residue was purified by preparative HPLC using MeCN/ammoniumacetate buffer (60:40) as eluent. The collected fractions werelyophilised to obtain 8 mg (13%) of the title compound. NMR (300 MHz):0.7-0.9 (m, 6H), 1.0-1.25 (m, 4H), 1.35-1.65 (m, 4H), 1.9 (s, 3H), 2.15(s, 3H), 2.95-3.1 (m, 4H), 3.25 (s, 2H), 3.5-3.85 (m, 4H), 4.75 (s, 2H),5.45 (s, 1H), 6.7 (s, 1H), 6.95-7.5 (m, 11H).

Example 41,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carbamoylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0520]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1; 50 mg, 0.082 mmol), glycinamide hydrochloride (27 mg, 0.24mmol) and N-methyl morpholine (44 μl, 0.4 mmol) were added to DCM (4ml). TBTU (42 mg, 0.13 mmol) was added and the mixture was stirred atroom temperature for 2 hours. The solvent was evaporated under reducedpressure and the residue was purified by preparative HPLC usingMeCN/ammonium acetate buffer (55:45) as eluent. The collected fractionswere lyophilised to obtain 7 mg (13%) of the title compound. NMR (300MHz): 0.7-0.9 (m, 6H), 1.0-1.3 (m, 4H), 1.4-1.65 (m, 4H), 3.25 (s, 2H),3.7-4.0 (m, 3H), 4.7-4.8 (m, 2H), 5.5 (s, 1H), 6.7 (s, 1H), 6.95-7.5 (m,11H).

Example 51,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carbamoyl-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0521]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1; 50 mg, 0.082 mmol), L-serinamide hydrochloride (35 mg, 0.25mmol) and N-methylmorpholine (44 μl, 0.4 mmol) were added to DCM (4 ml)and DMF (1 ml). TBTU (42 mg, 0.13 mmol) was added and the mixture wasstirred at room temperature for 2 hours. The solvents were evaporatedunder reduced pressure and the residue was purified by preparative HPLCusing MeCN/ammonium acetate buffer (60:40) as eluent. The collectedfractions were lyophilised to obtain 5 mg (9%) of the title compound.NMR (300 MHz): 0.7-0.9 (m, 6H), 1.0-1.35 (m, 4H), 1.4-1.65 (m, 4H), 2.15(s, 3H), 3.25b (s, 2H), 3.6-3.9 (m, 4H), 4.35-4.5 (m, 1H), 4.7-4.8 (m,2H), 5.6 (d, 1H), 6.7 (s, 1H), 6.95-7.55 (m, 11H).

Example 61,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-carbamoylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0522]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 17; 50 mg, 0.1 mmol), D-phenylglycinamide (18 mg, 0.12 mmol) and2,6-lutidine (58 μl, 0.5 mmol) were added to DCM (3 ml). TBTU (42 mg,0.13 mmol) was added and the reaction mixture was stirred for 3 hours atroom temperature The mixture was purified by column chromatography onsilica gel using EtOAc as eluent. The residue was dissolved in tolueneand was evaporated under reduced pressure. The residue was solved inMeCN/water (50/50) and the mixture was lyophilised to obtain 27 mg (42%)of the title compound. NMR (300 MHz): 0.7-0.9 (m, 6H), 1.0-1.3 (m, 4H),1.4-1.65 (m, 4H), 2.15 (s, 3H), 3.2 (s, 2H), 3.55-3.9 (m, 2H), 4.7 (ABq,2H), 5.5 (s, 1H), 6.75 (s, 1H), 6.95-7.5 (m, 11H).

Example 71,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(1,1-di-hydroxymethyl-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0523]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1; 50 mg, 0.082 mmol), tris(hydroxymethyl)aminomethane (30 mg,0.25 mmol) and 2,6-lutidine (58 μl, 0.5 mmol) were added to DCM (3 ml).TBTU (42 mg, 0.13 mmol) was added and the mixture was stirred for 4hours at room temperature The solvent was evaporated under reducedpressure and the residue was purified by preparative HPLC usingMeCN/ammonium acetate buffer (55:45) as eluent. The collected fractionswere lyophilised to obtain 5 mg (9%) of the title compound. NMR (300MHz): 0.7-0.9 (m, 6H), 1.0-1.3 (m, 4H), 1.4-1.65 (m, 4H), 2.15 (s, 3H),3.25 (s, 2H), 3.6-3.8 (m, 7H), 4.7-4.8 (m, 2H), 5.6 (s, 1H), 6.7 (s,1H), 6.95-7.5 (m, 11H).

Example 81,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(hydroxycarbamoyl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0524]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1; 50 mg, 0.082 mmol), glycine hydroxamic acid (22 mg, 0.24mmol) and 2,6-lutidine (58 μl, 0.5 mmol) were added to DCM (3 ml). TBTU(42 mg, 0.13 mmol) was added and the mixture was stirred for 3 hours atroom temperature The mixture was washed with water and the organic layerwas dried and evaporated under reduced pressure. The residue waspurified by preparative HPLC using MeCN/ammonium acetate buffer (60:40)as eluent. The collected fractions were lyophilised to obtain 7 mg (13%)of the title compound. NMR (500 MHz): 0.7-0.9 (m, 6H), 0.95-1.3 (m, 4H),1.4-1.7 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.7-3.95 (m, 4H), 4.6 (s,2H), 5.5 (s, 1H), 6.7 (s, 1H), 6.95-7.55 (m, 11H).

Example 91,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[N-(2,2,2-trifluoroethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0525]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 6; 50 mg, 0.072 mmol), trifluoroethylamine (8.5 mg, 0.086 mmol)and TBTU (27 mg, 0.084 mmol) were dissolved in DCM and 2,6-lutidine(0.020 ml, 0.18 mmol) was added. The reaction mixture was stirred atroom temperature for 2 hours and was filtered through a short silicacolumn. The product was further purified with preparative HPLC(MeCN/ammonium acetate buffer (50:50→100:0)) to give the title compound(45 mg, 81%/o). NMR (400 MHz, DMSO-d₆): 0.75 (m, 6 H), 0.95-1.46 (m,12H), 2.15 (s, 3 H), 3.28 (m, 2 H), 3.60-3.94 (m, 4 H), 4.73/4.84 (ABq,2 H), 5.56 (d, 1 H), 6.67 (s, 1 H), 6.85 (t, 1 H), 6.99 (d, 2 H),7.17-7.46 (8 H), 8.53 (t, 1 H), 8.61 (d, 1 H), 8.75 (t, 1 H).

Examples 10-17

[0526] The following examples were prepared by the procedure of Example9 using1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 6) and the appropriate amine.

Ex R NMR 400 MHz, DMSO-d₆ 10¹

0.74 (m, 6H), 0.95-1.45 (m, 12H), 1.85 (s, 1H), 2.16 (s, 3H), 3.00 (m,1H), 3.25-3.40 (br s, 5H), 3.45-3.85 (m, 4H), 4.72/4.84 (ABq, 2H), 5.60(d, 1H), 5.75 (s, 1H), 6.65 (s, 1H), 6.86 (t, 1H), 6.98 (d, 2H),7.17-7.46 (m, 8H), 7.76 (t, 1H), 8.58 (d, 1H), 8.66 (t, 1H) 11

0.74 (m, 6H), 0.96-1.48 (m, 12H), 2.15 (s, 3H), 3.28 (m, 1H), 3.64 (dd,1H), 3.80 (dd, 1H), 4.33 (t, 1H), 4.45 (t, 1H), 4.73/4.84 (ABq, 2H),5.55 (d, 1H), 6.67 (s, 1H), 6.86 (t, 1H), 6.99 (d, 2H), 7.18-7.46 (m,8H), 8.08 (t, 1H), 8.61 (d, 1H), 8.70 (t, 1H) 12

0.74 (m, 6H), 0.97 (t, 3H), 0.95-1.48 (m, 12H), 2.15 (s, 3H), 3.05 (m,2H), 3.24 (m, 2H), 3.65 (dq, 2H), 4.74/4.84 (ABq, 2H), 5.53 (d, 1H),6.67 (s, 1H), 6.86 (t, 1H), 6.99 (d, 2H), 7.17-7.46 (m, 8H), 7.73 (t,1H), 8.62 (d, 1H), 8.68 (t, 1H) 13

0.74 (m, 6H), 0.94-1.48 (m, 12H), 2.15 (s, 3H), 3.65-3.85 (m, 2H), 3.70(s, 3H), 4.14 (t, 2H), 4.72/4.83 (ABq, 2H), 5.60 (d, 1H), 6.60-7.01 (m,7H), 7.15-7.45 (m, 8H), 8.17 (t, 1H), 8.60 (d, 1H), 8.70 (t, 1H) 14

0.75 (m, 6H), 0.95-1.46 (m, 12H), 2.15 (s, 3H), 3.20 (s, 3H), 3.30 (t,2H), 3.60 (dd, 1H), 3.76 (dd, 1H), 4.74/4.86 (ABq, 2H), 5.54 (d, 1H),6.67 (s, 1H), 6.86 (t, 1H), 6.99 (d, 2H), 7.17-7.45 (m, 8H), 7.85 (t,1H), 8.61 (d, 1H), 8.69 (t, 1H) 15¹

0.75 (m, 6H), 0.95-1.46 (m, 12H), 2.13 (s, 3H), 2.75 (t, 2H), 3.58 (dd,1H), 3.74 (dd, 1H), 4.74/4.85 (ABq, 2H), 5.53 (d, 1H), 6.66 (s, 1H),6.85 (t, 1H), 6.99 (d, 2H), 7.16-7.47 (m, 10H), 7.71 (m, 2H), 7.89 (t,1H), 8.65 (d, 1H), 8.69 (t, 1H) 16¹

0.75 (m, 6H), 0.95-1.46 (m, 12H), 2.15 (s, 3H), 2.62 (s, 6H), 2.91 (m,2H), 3.13 (m, 2H), 3.61 (dd, 1H), 3.76 (dd, 1H), 4.74/4.84 (ABq, 2H),5.56 (d, 1H), 6.67 (s, 1H), 6.86 (t, 1H), 6.99 (d, 2H), 7.14-7.48 (m,8H), 7.91 (t, 1H), 8.60 (d, 1H), 8.68 (t, 1H) 17¹

0.74 (m, 6H), 0.96-1.46 (m, 12H), 2.15 (s, 3H), 3.60 (m, 1H), 3.75 (m,1H), 4.73/4.84 (ABq, 2H), 5.55 (d, 1H), 6.65 (s, 1H), 6.85 (t, 1H),7.00-7.45 (m, 12H), 8.00 (t, 1H), 8.52 (d, 1H), 8.61 (m, 1H), 8.69 (t,1H)

Example 181,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0527]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 8; 60 mg, 0.094 mmol) and 1-amino-1-deoxy-D-glucitol (20 mg,0.11 mmol) were dissolved in DMF (2 ml) (40° C. for a few minutes wasrequired). 2,6-Dimethylpyridine (22 μl, 0.19 mmol) and HATU (43 mg,0.111 mmol) were added at room temperature to the solution and themixture was stirred for 30 minutes. The solvent was evaporated underreduced pressure and the product was purified by preparative HPLC usinga MeCN/ammonium acetate buffer gradient (5/95 to 100/0) as eluent togive the title compound, 52 mg (69%). NMR (400 MHz): 0.77-0.85 (brt,6H), 1.0-1.35 (m, 8H), 1.35-1.6 (m, 4H), 2.15 (s, 3H), 3.16-3.27 (m,3H), 3.51 (dd, 1H) 3.54-3.86 (m, 8H), 4.70 (ABq, 2H), 5.52 (s, 1H), 6.70(s, 1H), 6.98 (t, 1H), 7.11 (brd, 2H), 7.24-7.41 (m, 6H), 7.44 (brd,2H); m/z 802.5.

Example 191,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0528]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1; 40 mg, 0.065 mmol), 1-amino-1-deoxy-D-glucitol (17 mg, 0.094mmol) and DIPEA (55 μl , 0.32 mmol) were dissolved in DM (2 ml) (40° C.for a few minutes was required). TBTU (25 mg, 0.079 mmol) was added atroom temperature to the solution and the mixture was stirred over night.The solvent was evaporated under reduced pressure and the product waspurified by preparative HPLC using an MeCN/ammonium acetate buffergradient (5/95 to 100/0) as eluent to give the title compound, 31 mg(61%). NMR (400 MHz): 0.75-0.90 (m, 6H), 1.0-1.35 (m, 4H), 1.35-1.7 (m,4H), 2.15 (s, 3H), 3.17-3.27 (m, 3H), 3.46-3.96 (m, 9H), 4.70 (ABq, 2H),5.52 (s, 1H), 6.71 (s, 1H), 6.97 (t, 1H), 7.09 (brd, 2H), 7.23-7.50 (m,8H); m/z 774.4.

Example 201,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(3-morpholinopropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0529]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1;40 mg, 0.065 mmol), 3-morpholinopropylamine (11 mg, 0.079mmol) and N-methylmorpholine (14.4 μl, 0.13 mmol) were dissolved in DCM(2 ml). HATU (34 mg, 0.089 mmol) was added and the mixture was kept atroom temperature over night. The product was purified using an ISOLUTEcolumn (Silica, 2 g) and eluted in 5 steps, 10 ml DCM, 10 ml DCM:EtOAc8:2, 10 ml EtOAc, 10 ml EtOAc:MeOH (saturated with NH₃) and once againwith 10 ml EtOAc:MeOH (saturated with NH₃). The title compound wascollected from the fourth step, 35 mg (72%). NMR (400 MHz): 0.74-0.90(m, 6H), 1.0-1.35 (m, 4H), 1.35-1.7 (m, 4H), 1.76-1.9 (m, 2H), 2.15 (s,3H), 2.65-3.04 (m, 6H), 3.24 (brs, 2H), 3.6-3.9 (m, 8H), 4.72 (ABq, 2H),5.36 (s, 1H), 6.72 (s, 1H), 6.97 (t, 1H), 7.10 (brd, 2H), 7.23-7.50 (m,8H); m/z 737.4.

Examples 21-39

[0530] The following examples were prepared by the procedure of Example20 using1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-carboxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1) and the appropriate amine.

Ex R NMR 400 MHz m/z 21

0.75-0.87 (m, 6H), 1.01-1.35 (m, 4H), 1.35-1.67 (m, 4H), 2.15 (s, 3H),2.81 (t, 2H), 3.23 (brs, 2H), 3.40-3.53 (m, 2H), 3.60-3.86 (m, 2H), 4.70(ABq, 2H), 5.38 (s, 1H), 6.71 (s, 1H), 6.85 (s, 1H), 6.97 (t, 1H), 7.09(brd, 2H), 7.27 (t, 2H), 7.31-7.43 (m, 6H), 8.21 (s, 1H) 704.5 22

0.74-0.87 (m, 6H), 1.0-1.3 (m, 4H), 1.37-1.66 (m, 4H), 2.16 (s, 3H),2.69 (s, 6H), 3.05-3.15 (m, 4H), 3.23 (brs, 2H), 3.55-3.9 (m, 2H), 4.70(ABq, 2H), 5.47 (s, 1H), 6.71 (s, 1H), 6.97 (t, 1H), 7.09 (brd, 2H),7.23-7.48 (m, 8H) 760.4 23

0.73-0.86 (m, 6H), 1.0-1.3 (m, 4H), 1.35-1.65 (m, 4H), 2.15 (s, 3H),3.21 (brs, 2H), 3.54-3.9 (m, 4H), 3.94-4.06 (m, 2H), 4.69 (ABq, 2H),5.51 (s, 1H), 6.68-6.85 (m, 5H), 6.96 (t, 1H), 7.09 (brd, 2H), 7.22-7.34(m, 5H), 7.37-7.46 (m, 3H) 746.4 24

0.75-0.85 (m, 6H), 1.0-1.27 (m, 4H), 1.36-1.66 (m, 4H), 2.15 (s, 3H),3.23 (brs, 2H), 3.45 (ABq, 2H), 3.6-4.05 (m, 6H), 4.70 (ABq, 2H), 5.54(s, 1H), 6.71 (s, 1H), 6.86 (brs, 4H), 6.96 (t, 1H), 7.09 (brd, 2H),7.23-7.37 (m, 5H), 7.40 (s, 1H), 7.45 (brd, 2H) 788.4 25

0.76-0.84 (m, 6H), 1.0-1.3 (m, 4H), 1.3-1.67 (m, 13H), 2.16 (s, 3H),3.20 (brs, 2H), 3.58-3.9 (m, 2H), 4.34 (brs, 2H), 4.72 (ABq, 2H), 5.53(s, 1H), 6.71 (s, 1H), 6.78 (d, 1H), 6.96 (t, 1H), 7.06-7.16 (m, 3H),7.22-7.47 (m, 10H) 815.5 26

0.72-0.9 (m, 6H), 0.95-1.35 (m, 4H), 1.35-1.67 (m, 4H), 2.13 (s, 3H),3.21 (brs, 2H), 3.57-3.9 (m, 2H), 4.46 (brs, 2H), 4.70 (ABq, 2H), 5.27(brs, 2H), 5.51 (s, 1H), 6.68-6.73 (m, 1H), 6.96 (t, 1H), 7.05-7.15 (m,2H), 7.20-7.54 (m, 15H), 7.68-7.79 (m, 2H) 876.4 27

(600 MHz, 1:1 diastereomeric mixture) 0.74-0.82 (m, 6H), 1.0-1.3 (m,4H), 1.3-1.65 (m, 4H), 2.15 (s, 3H), 3.04 (s, 1.5H), 3.12 (s, 1.5H),3.18-3.3 (m, 3H), 3.35-3.44 (m, 1H), 3.55-3.9 (m, 2H), 3.98 (dd, 0.5H),4.04 (dd, 0.5H), 4.63-4.74 (m, 2H), 5.48 (s, 0.5H), 5.50 (s, 0.5H), 6.42(dd, 0.5H), 6.55 (dd, 0.5H), 6.62 (d, 0.5H), 6.66-6.72 (m, 2.5H), 6.95(t, 1H), 7.08 (brd, 2H), 7.23-7.40 (m, 8H) 774.5 28

(600 MHz) 0.75-0.83 (m, 6H), 1.0-1.3 (m, 4H), 1.35-1.63 (m, 4H), 2.15(s, 3H), 3.14-3.44 (m, 6H), 3.59-3.88 (m, 3H), 4.69 (ABq, 2H), 5.50 (s,1H), 6.70 (s, 1H), 6.95 (t, 1H), 7.08 (d, 2H), 7.24 7.32 (m, 3H), 7.34(t, 2H), 7.39 (s, 1H), 7.43 (brd, 2H) 684.4 29

(600 MHz) 0.77 (brt, 6H), 0.95-1.28 (m, 4H), 1.33-1.60 (m, 4H), 2.14 (s,3H), 2.77-2.89 (m, 2H), 3.18 (brs, 2H), 3.39-3.50 (m, 2H), 3.50-3.85 (m,5H), 4.66 (ABq, 2H), 5.43 (s, 1H), 6.68-6.72 (m, 2H), 6.77 (s, 1H), 6.94(t, 1H), 6.99 (d, 1H), 7.06 (brd, 2H), 7.16 (d, 1H), 7.2-7.36 (m, 7H),7.38 (s, 1H) 783.4 30

(600 MHz) 0.75-0.85 (m, 6H), 1.0-1.27 (m, 4H), 1.38-1.63 (m, 4H), 2.17(s, 3H), 3.22 (brs, 2H), 3.33-3.39 (m, 1H), 3.47-3.53 (m, 1H), 3.57-3.96(m, 6H), 4.69 (ABq, 2H), 5.38 (s, 1H), 6.71 (s, 1H), 6.95 (t, 1H), 7.08(brd, 2H), 7.23-7.40 (m, 8H) 753.5 31

(600 MHz) 0.74-0.83 (m, 6H), 1.0-1.28 (m, 4H), 1.38-1.62 (m, 4H), 1.7(m, 2H), 2.14 (s, 3H), 2.44-2.56 (m, 2H), 2.56-2.86 (m, 5H), 2.86-3.10(m, 4H), 3.22 (brs, 2H), 3.25 (t, 2H), 3.57-3.87 (m, 4H), 4.69 (ABq,2H), 5.38 (s, 1H), 6.70 (s, 1H), 6.96 (t, 1H), 7.08 (brd, 2H), 7.26 (t,2H), 7.30-7.40 (m, 4H), 7.43 (d, 2H) 750.6 32

(600 MHz) 0.74-0.85 (m, 6H), 1.0-1.3 (m, 4H), 1.37-1.65 (m, 4H), 2.17(s, 3H), 2.81 (t, 2H), 3.22 (brs, 2H), 3.32-3.41 (m, 1H), 3.50-3.59 (m,1H), 3.6-3.85 (m, 2H), 4.68 (ABq, 2H), 5.40 (s, 1H), 6.72 (s, 1H), 6.97(t, 1H), 7.09 (d, 2H), 7.17 (d, 2H), 7.27 (t, 2H), 7.31-7.37 (m, 5H),7.39 (s, 1H), 7.69 (d, 2H) 793.5 33

(600 MHz, 1:1 diastereomeric mixture) 0.72-0.84 (m, 6H), 0.98-1.28 (m,4H), 1.36-1.61 (m, 4H), 2.13-2.16 (m, 3H), 2.68 (dd, 0.5H), 2.82 (dd,0.5H), 3.02-3.14 (m, 1.H), 3.14-3.23 (m, 2H), 3.38-3.45 (m, 1H),3.46-3.53 (m, 1H), 3.55-3.9 (m, 8H), 4.61-4.86 (m, 3H), 5.48 (s, 0.5H),5.49 (s, 0.5H), 6.36 (s, 0.5H), 6.37 (s, 0.5H), 6.65 (s, 0.5H),6.69-6.71 (m, 1H), 6.75 (s, 0.5H), 6.95 (t, # 1H), 7.07 (brd, 2H),7.18-7.40 (m, 8H) 807.6 34

(600 MHz) 0.74-0.83 (m, 6H), 0.91-1.24 (m, 6H), 1.38-1.66 (m, 16H), 2.16(s, 3H), 2.52-2.74 (m, 2H), 3.0 (dd, 1H), 3.11 (dd, 1H), 3.22 (brs, 2H),3.55-3.90 (m, 2H), 3.96 (brd, 2H), 4.68 (ABq, 2H), 5.44 (s, 1H), 6.71(s, 1H), 6.95 (t, 1H), 7.08 (brd, 2H), 7.26 (t, 2H), 7.28-7.32 (m, 1H),7.34 (t, 2H), 7.38 (s, 1H), 7.42 (brd, 2H) 807.6 35

(600 MHz) 0.71 (brt, 6H), 0.93-1.18 (m, 4H), 1.18-1.58 (m, 4H), 2.04 (s,3H), 3.0-3.2 (m, 4H), 3.49-3.76 (m, 2H), 3.94-4.04 (m, 2H), 5.32-5.34(m, 1H), 6.45 (s, 1H), 6.86-6.94 (m, 3H), 7.16 (t, 2H), 7.27-7.38 (m,4H), 7.47 (brd, 2H), 7.82 (brd, 2H), 8.05 (brd, 2H) 788.5 36

(600 MHz) 0.73-0.83 (m, 6H), 0.98-1.3 (m, 4H), 1.3-1.64 (m, 4H), 2.14(s, 3H), 3.05-4.0 (m, 8H), 4.66 (ABq, 2H), 5.46 (s, 1H), 6.69 (s, 1H),6.92 (t, 1H), 6.95 (t, 1H), 7.08 (brd, 2H), 7.2-7.3 (m, 5H), 7.35-7.39(m, 3H), 8.44 (d, 2H) 774.5 37

0.73-0.84 (m, 6H), 0.98-1.3 (m, 4H), 1.3-1.65 (m, 4H), 2.14 (s, 3H),3.04-4.1 (m, 8H), 4.66 (ABq, 2H), 5.47 (s, 1H), 6.70 (s, 1H), 6.97 (brt,2H), 7.02 (d, 1H), 7.09 (brd, 2H), 7.2-7.32 (m, 5H), 7.35-7.43 (m, 3H),7.72 (brt, 1H), 8.12 (brd, 1H) 773.5 38

0.74-0.85 (m, 6H), 0.86-1.3 (m, 4H), 1.3-1.65 (m, 4H), 2.15 (s, 3H),3.21 (brs, 2H), 3.51-4.12 (m, 6H), 4.69 (ABq, 2H), 5.53 (s, 1H), 6.71(s, 1H), 6.90 (d, 2H), 6.96 (t, 1H), 7.08 (d, 2H), 7.22-7.34 (m, 5H),7.36-7.43 (m, 3H), 7.79 (d, 2H) 773.5 39

0.74-0.85 (m, 6H), 1.0-1.3 (m, 4H), 1.3-1.66 (m, 4H), 2.16 (s, 3H),3.13-3.45 (m, 8H), 3.6-4.0 (m, 4H), 4.70 (ABq, 2H), 5.45 (s, 1H), 6.72(s, 1H), 6.96 (t, 1H), 7.09 (brd, 2H), 7.22-7.45 (m, 8H) 722.5

Example 401,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(3-aminobenzyl)carbamoyl]benzyl}carbarmoylmethoxy)-2,3,4,5-tetrahydro-1.5-benzothiazepine

[0531]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[3-(t-butoxy-carbonylamino)benzyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 25; 10 mg, 0.012 mmol) was dissolved in EtOAc (15 ml) saturatedwith HCl (gas). The reaction mixture was left for 1 hour. The solventwas evaporated under reduced pressure and the residue was freeze-driedto give the title compound in quantitative yield. NMR (600 MHz)0.67-0.76 (m, 6H), 0.93-1.17 (m, 4H), 1.31-1.54 (m, 4H), 2.05 (s, 3H),3.14 (brs, 2H), 3.44-3.86 (m, 2H), 4.25 (d, 1H), 4.40 (d, 1H), 4.64(ABq, 2H), 5.40 (s, 1H), 6.62 (s, 1H), 6.88 (t, 1H), 7.01 (brd, 2H),7.05-7.13 (m, 3H), 7.18 (t, 2H), 7.23-7.33 (m, 5H), 7.37 (d, 2H); m/z715.5.

Example 411,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(piperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0532]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(N″-t-butoxycarbonylpiperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 34; 7.3 mg, 0.00904 mmol) was dissolved in ethyl acetatesaturated with hydrogen chloride gas (15 ml). After 1.5 hours thereaction mixture was evaporated under reduced pressure. The product waslyophilised giving 4.6mg (68%) of the title compound. NMR (400 MHz):0.74-0.87 (m, 6H), 0.9-1.7 (m, 10H), 1.73-1.9 (m, 3H), 2.15 (s, 3H),2.83-2.98 (m, 2H), 3.04-3.40 (m, 6H), 3.6-3.9 (m, 2H), 4.71 (ABq, 2H),5.42 (s, 1H), 6.72 (s, 1H), 6.97 (t, 1H), 7.09 (brd, 2H), 7.22-7.49 (m,8H); 707.6.

Example 411,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(4-amidinobenzyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepineAcetate Salt (Compound 1) Example 421,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-(N-{(R)-α-[N′-(4-amidinobenzyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepineAcetate Salt (Compound 2)

[0533]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[4-(N²-benzyloxycarbonylamidino)benzyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 26; 18 mg, 0.020 mmol) was dissolved in ethanol (10 ml),palladium on activated carbon (5%, 10 mg) was added and a few drops ofacetic acid. The mixture was treated under a hydrogen atmosphere for acouple of hours. The mixture was filtered through diatomaceous earth andthe solvent was evaporated under reduced pressure. The reaction was notcomplete. The above had to be repeated two times. The mixture waspurified by preparative HPLC using a MeCN/ammonium acetate buffergradient (5/95 to 100/0) as eluent to give Compound 1, 1 mg (6%) andCompound 2, 1 mg, 6%. Compound 1, m/z 742.5. Compound 2 NMR (400 MHz):0.8-0.85 (m, 6H), 1.0-1.7 (m, 8H), 1.9 (s, 3H(acetate)), 3.23 (bs, 2H),3.6-3.85 (m, 2H), 4.49 (ABq, 2H), 4.66 (s, 2H), 5.51 (s, 1H), 6.94 (d,2H), 7.04 (d, 2H), 7.13 (dd, 1H), 7.23 (brt, 2H), 7.3-7.46 (m, 6H), 7.53(d, 1H), 7.69 (d, 2H).

Example 431,1-Dioxo-3.3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0534]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(carboxy)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 2 of WO 02/50051; 81 mg, 0.124 mmol),(2R,3R,4R,5S)-6-aminohexane-1,2,3,4,5-pentol (26.9 mg, 0.15 mmol) and2,6-dimethylpyridine (28.8 μl, 0.25 mmol) was dissolved in DMF (3 ml).TBTU (48 mg, 0.15 mmol) was added. The reaction mixture was stirred for3-4 hours. The solvent was evaporated under reduced pressure. Theproduct was purified by preparative HPLC using a MeCN/ammonium acetatebuffer gradient (5/95 to 100/0) as eluent to give 59 mg (58%) of thetitle compound. NMR (600 MHz) 0.79 (t, 6H), 1.0-1.25 (m, 8H), 1.36-1.54(m, 4H), 2.13 (s, 3H), 3.19 (dd, 1H), 3.23 (bs, 2H), 3.49 (dd, 2H),3.55-3.85 (m, 8H), 4.68 (ABq, 2H), 5.38 (s, 1H), 6.68 (s, 1H), 6.74 (d,2H), 6.96 (t, 1H), 7.10 (brd, 2H), 7.21-7.29 (m, 4H), 7.37 (s, 1H).

Example 441,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-methyl-N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0535]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 1 ofWO 02/50051; 40 mg, 0.063 mmol),(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol (16 mg, 0.082 mmol)and N-Methylmorpholine (30 mg, 0.30 mmol) was dissolved in DMF (1 ml).TBTU (25 mg, 0.078 mmol) was added. The mixture was stirred for 1 hour.The solvent was evaporated under reduced pressure. The product waspurified by preparative HPLC using a MeCN/ammonium acetate buffer togive, after lyophilisation, 6 mg (12%) of the title compound. M/z 817.2.

[0536] Preparation of Starting Materials

[0537] The starting materials for the Examples above are eithercommercially available or are readily prepared by standard Methods fromknown materials. For Example, the following reactions are anillustration, but not a limitation, of some of the starting materialsused in the above reactions.

[0538] Method 1

[0539]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0540]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 2; 50 mg, 0.078 mmol) was dissolved in DMF (1.5 ml). Sodiummethanethiolate (20 mg, 0.29 mmol) was added and the mixture was stirredfor 1.5 hours at 50° C. Acetic acid (40 mg) was added and the solventwas evaporated under reduced pressure. The residue was purified bypreparative HPLC using MeCN/ammonium acetate buffer (45:55) as eluent togive the title compound 29 mg (61%). NMR (400 MHz, DMSO-d₆): 0.7-0.8 (m,6H), 0.9-1.6 (m, 8H), 2.2 (s, 3H), 3.1-3.7 (m, 4H), 4.6-4.8 (m, 3H), 6.7(s, 1H), 6.8-7.4 (m, 11H), 8.3 (d, 1H).

[0541] Method 2

[0542]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0543] The title compound was synthesised from1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-α-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 3) by the procedure of Example 9, except that the water layerwas extracted with EtOAc. The product was purified by preparative HPLCusing an MeCN/ammonium acetate buffer gradient (5/95 to 100/0) aseluent. NMR (400 Mz): 0.75-0.83 (m, 6H), 1.0-1.25 (m, 4H), 1.32-1.52 (m,3H), 1.55-1.70 (m, 1H), 3.20 (ABq, 2H), 3.65-3.83 (m, 2H), 4.62 (ABq,2H), 5.68 (d, 1H), 7.04-7.15 (m, 4H), 7.3-7.5 (m, 8H), 7.87 (brd, 1H);m/z 643.1.

[0544] Method 3

[0545]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-α-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0546]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(50 mg, 0.098 mmol) was dissolved in DCM (2 ml). Methyl(2R)-amino(phenyl)acetate hydrochloride (23.7 mg, 0.12 mmol) and DIPEA(0.068 ml, 0.39 mmol) was added and the reaction was stirred for 2minutes. TBTU (38 mg, 0.12 mmol) was added and the mixture was stirredfor 1.5 hours at room temperature. The mixture was directly put on anISOLUTE-column (Silica, 2 g) and eluted stepwise with 10 ml DCM/EtOAc100:1, 9:1 then 8:2. 58 mg (90%) of the title compound was obtained. M/z657.5

[0547] Method 4

[0548]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0549]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 5; 0.34 g) and sodium hydroxide (0.3 g) were dissolved inethanol and the mixture was heated to reflux for 1 hour. Acetic acid (1ml) was added and the solvent was removed at reduced pressure. Theresidue was partitioned between DCM/H₂O and the organic layer wasseparated and dried. Trituration of the residue with n-hexane gave thetitle compound 0.29 g (90%) as a solid. NMR (500 MHz, CDCl₃): 0.7-0.8(m, 6H), 1.0-1.7 (m, 8H), 3.1-3.2 (m, 2H), 3.6 (br s, 2H), 4.6 (s, 2H),6.9-7.1 (m, 4H), 7.2 (m, 2H), 7.5 (s, 1H).

[0550] Method 5

[0551]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0552] A mixture of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO 96/16051; 0.3 g), ethyl bromoacetate (0.14 g), sodium carbonate (0.3g), tetrabutylammonium bromide (0.02 g) in MeCN (10 ml) were refluxedfor 4 hours. The solvent was removed under reduced pressure. The residuewas partitioned between DCM/H₂O and the organic layer was separated. Thesolvent was evaporated and the residue was purified by chromatography(DCM/EtOAc, 90:10) to give the title compound 0.34 g (95%). NMR (500 Mz;CDCl₃): 0.7-0.9 (m, 6H), 1.0-1.8 (m, 11 H), 3.2 (m, 2H), 3.6-3.8 (br s,2H), 4.3 (q, 2H), 4.7 (s, 2H), 7.0-7.1 (m, 3 H), 7.15 (s, 1H), 7.3 (m,2H), 7.4 (s, 1H).

[0553] Method 6

[0554]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0555]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(t-butoxycarbonyl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 7; 120 mg, 0.17 mmol) was dissolved in DCM (2 ml). TFA (0.7 ml)was added and the mixture was stirred at room temperature for 3 h. Thereaction mixture was evaporated under reduced pressure. The residue waspurified by preparative HPLC using MeCN/ammonium acetate buffer (50:50)as eluent to give the title compound 95 mg (85%). NMR (300 MHz,DMSO-d₆): 0.7-0.8 (m, 6H), 0.9-1.6 (m, 12H), 2.2 (s, 3H) 3.2-3.3 (m,2H), 3.5-3.8 (m, 4H), 4.8 (ABq, 2H), 5.6 (d, 1H), 6.7 (s, 1H), 6.8-7.5(m, 11H), 8.5-8.7 (m, 2H).

[0556] Method 7

[0557]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0558]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 8; 110mg, 0.17 mmol), glycine tert-butyl ester (30 mg, 0.23 mmol) and DIPEA(120 mg, 0.93 mmol) were dissolved in DCM (2 ml). The mixture wasstirred for 5 mins at room temperature. TBTU (72 mg, 0.22 mmol) wasadded and the mixture was stirred for 1 h at room temperature. Thesolvent was evaporated at reduced pressure and the residue was placed ona silica column and the product was eluted with DCM/EtOAc (90:10) togive the title compound 122 mg (94%). NMR (300 MHz): 0.7-0.8 (m, 6H),1.0-1.6 (m, 21H), 2.2 (s, 3H) 3.2 (s, 2H), 3.7-4.0 (m, 4H), 4.6 (ABq,2H), 5.6 (d, 1H), 6.4 (t, 1H), 6.6 (s, 1H), 6.9-7.5 (m, 11H), 8.1 (d,1H).

[0559] Method 8

[0560]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0561]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 9; 300mg, 0.46 mmol) was dissolved in methanol (5 ml). NaOH (100 mg in 0.2 mlwater) was added to the solution and the mixture was stirred at roomtemperature for 1 hour. Acetic acid (0.3 ml) was added. The solvent wasevaporated under reduced pressure and the residue was extracted withDCM/water. The DCM layer was separated, dried and evaporated underreduced pressure to give the title compound 270 mg (92%). NMR, 500 MHz):0.7-0.8 (m, 6H), 1.0-1.6 (m, 12H), 2.1 (s, 3H) 3.2 (brs, 2H), 3.6-3.8(m, 2H), 4.6 (s, 2H), 5.6 (d, 1H), 6.6 (s, 1H), 6.9-7.5 (m, 11H), 7.8(d, 1H).

[0562] Method 9

[0563]1,1-Dioxo-33-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0564]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 10; 250 mg, 0.49 mmol), (R)-2-phenylglycine methyl esterhydrochloride (120 mg, 0.60 mmol) and DIPEA (300 mg, 2.3 mmol) weredissolved in DCM (10 ml) and the mixture was stirred for 5 min in roomtemperature. TBTU (210 mg, 0.65 mmol) was added and the mixture wasstirred for 30 min at room temperature. The solvent was evaporated underreduced pressure and the residue was placed on a silica column and theproduct was eluted with DCM/EtOAc (90:10) to give the title compound 306mg (95%). NMR (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 12H), 2.1 (s, 3H)3.2 brs, 2H), 3.6-3.8 (m, 5H), 4.6 (ABq, 2H), 5.6 (d, 1H), 6.6 (s, 1H),6.9-7.5 (m, 11H), 7.9 (d, 1H).

[0565] Method 10

[0566]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0567]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 11; 500 mg, 0.93 mmol) was dissolved in DMF (10 ml). Sodiummethanethiolate (200 mg, 2.85 mmol) was added and the mixture wasstirred for 2 hours at 50° C. Acetic acid (0.4 ml) was added and the.solvent was evaporated under reduced pressure. The residue was extractedwith EtOAc/water. The EtOAc layer was separated, dried and evaporatedunder reduced pressure to give the title compound 450 mg (96%). NMR (300MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 12H), 2.2 (s, 2H), 3.2 (brs, 2H), 3.7(brs, 2H), 4.8 (s, 2H), 6.6 (s, 1H), 6.9-7.1 (m, 3H), 7.2-7.4 (m, 3H).

[0568] Method 11

[0569]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0570]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 12; 2.2 g, 3.88 mmol) was dissolved in ethanol (15 ml). NaOH(0.8 g in 1.5 ml water) was added to the solution and the mixture wasstirred for 30 min at room temperature. Acetic acid (2 ml) was added.The solvent was evaporated under reduced pressure and the residue wasextracted with EtOAc/water. The EtOAc layer was separated, dried andevaporated under reduced pressure to give the title compound 2.0 g(95%). NMR (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.5 (m, 12H), 3.2 (brs, 2H),3.7 (brs, 2H), 4.7 (s, 2H), 7.0-7.3 (m, 6H), 7.4 (s, 1H).

[0571] Method 12

[0572]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0573]1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(synthesised by the procedure of WO9616051 for the corresponding3-butyl-3-ethyl analogue; 2.0 g, 4.16 mmol), ethyl bromoacetate (0.84 g,5.03 mmol), sodium carbonate (2.0 g, 18.9 mmol) and tetrabutylammoniumbromide (80 mg, 0.25 mmol) were added to MeCN (20 ml). The mixture wasrefluxed for 2 hours and then evaporated under reduced pressure. Theresidue was extracted with DCM/water. The DCM layer was separated andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel. The product was eluted with DCM /EtOAc(90:10) to give the title compound 2.2 g (93%). NMR (400 MHz) 0.7-0.8(m, 6H), 1.0-1.6 (m, 15H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.3 (q, 2H),4.7 (s, 2H), 7.0-7.3 (m, 6H), 7.4 (s, 1H).

[0574] Method 13

[0575] 5,6-Dimethoxy-2.3-dihydrobenzofuran-2-ylmethylamine

[0576] 5,6-Dimethoxy-2,3-dihydrobenzofuran-2-carbonitrile (Method 16;2.63 g, 12.94 mmol) was dissolved in ethanol (700 ml) and hydrochloricacid (conc, 2.3 ml) and Pd on charcoal (10%, 1 g) were added. Themixture was hydrogenated under 3.5 atmosphere of hydrogen at 72° C. for3 days. The mixture was filtered and the solvent was evaporated underreduced pressure. The residue was dissolved in water and washed oncewith diethyl ether. The pH of the aqueous phase was adjusted to 10-11with NaOH(aq) and the resulting solution was extracted several timeswith diethyl ether, then with DCM. The organic layers were dried,filtered and evaporated under reduced pressure. The diethyl etherextraction gave 0.6 g (22%) of pure product and the DCM extraction gave2.0 g (74%) of pure product. NMR (400 MHz) 2.80-2.87 (m, 3H), 3.21 (dd,1H), 3.74 (s, 3H), 3.76 (s, 3H), 4.72-4.82 (m, 1H), 6.47 (s, 1H), 6.82(s, 1H).

[0577] Method 14

[0578] N-(2-Aminoethyl)-N′-pyrimidin-2-ylurea

[0579] Phenyl pyrimidin-2-ylcarbamate (121.3 g, 0.57 mol) andethane-1,2-diamine (380 ml, 5.7 mol) were mixed and cooled with anice-bath. Sodium (0.5 g, 0.0217 mol) was added in small pieces. Thereaction was exothermic and the temperature went up to 38° C. and thenthe temperature was kept at approximately 8° C. for 5 days. Theremaining ethane-1,2-diamine was evaporated under reduced pressure andco-evaporated with toluene three times. The residue was dissolved inethanol (99%, 1 l)and filtered. Hydrochloric acid (conc, 78 ml) wasadded. The mixture was kept at 8° C. overnight. The crystals formed werecollected and washed with ethanol (99%/o) to yield the product as aHCl-salt in 97% (120 g) yield. NMR (400 MHz) 3.15 (t, 2H), 3.27 (brs,NH), 3.63 (t, 2H), 7.05 (t, 1H), 8.57 (d, 2H).

[0580] Method 15

[0581] N-(2-Aminoethyl)-N′-pyridin-2-ylurea

[0582] Phenyl pyridin-2-ylcarbamate (163.5 g, 0.929 mol) andethane-1,2-diamine (620 ml, 9.29 mol) was mixed and cooled with anice-bath. Sodium (0.5 g, 0.0217 mol) was added in small pieces. Thereaction was exothermic and the temperature went up to 42° C. and thenthe temperature was kept at 8° C. for 5 days. The remainingethane-1,2-diamine was evaporated under reduced pressure andco-evaporated with toluene three times. The residue was dissolved inMeCN and the crystals formed were filtered off. Hydrochloric acid (conc,110 ml) was added to the solution. The crystals formed were collectedand washed with MeCN:MeOH 1:1 to yield the product as a HCl-salt in 72%(145.1 g) yield. NMR (400 MHz) 3.16 (t, 2H), 3.28 (brs, NH), 3.60 (t,2H), 7.40-7.47 (m, 2H), 8.27-8.36 (m, 2H).

[0583] Method 16

[0584] 5,6-Dimethoxy-2,3-dihydrobenzofuran-2-carbonitrile

[0585] 2-Hydroxy-4,5-dimethoxybenzaldehyde (25.5 g, 0.14 mol),chloroacetonitrile (12.4 g, 0.168 mol) and potassium carbonate (116 g,0.84 mol) was dissolved in DMF (150 ml). The mixture was stirred for 10minutes at 165° C. The solvent was concentrated under reduced pressure.The residue was separated in two parts, water was added and the firstpart was extracted with diethyl ether and the second part extracted withDCM. The second part was evaporated under reduced pressure and dissolvedin ether and washed once with water. The organic layers was combined andevaporated under reduced pressure. The crystalline residue was washedwith warm methanol (700 ml) and filtered. The residue was dissolved in225 ml DCM and diethyl ether (450 ml) was added. The crystals formed wascollected giving 14.6 g (51% yield) of product. Mp. 162° C.

[0586] Method 17

[0587]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methlthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0588] To1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 18; 478 mg, 0.95 mmol) was added THF (15 ml), water (3 ml) andLiOH (34 mg, 1.4 mmol). The reaction was then stirred for 1 hour. Thenacetic acid (0.2 ml) was added along with water (10 ml) and DCM (10 ml)The aqueous layer was then extracted three times with DCM. The combinedorganic phases were then dried and concentrated to give the titlecompound 450 mg (99%). NMR (400 MHz) 0.7-0.9 (m, 6H), 1.0-1.7 (m, 8H),2.2 (s, 3H), 3.2 (q, 2H), 3.7 (m, 2H), 4.8 (s, 2H), 6.65 (s, 1H), 6.95(t, 1H), 7.05 (d, 2H), 7.25 (t, 2H), 7.35 (s, 1H), 8.4 (brs, 1H).

[0589] Method 18

[0590]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-15-benzothiazepine

[0591] To1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 19; 500 mg, 1.2 mmol) was added MeCN (30 ml), tetrabutylammoniumbromide (30 mg, 0.08 mmol), anhydrous sodium carbonate (500 mg, 4.7mmol), ethyl bromoacetate (0.14 ml, 1.26 mmol) and caesium carbonate (20mg, 0.06 mmol). This reaction mixture was then stirred over night at 80°C. Then the solvent was removed under reduced pressure, water and DCMwere added and the aqueous phase was extracted three times with DCM. Thecombined organic phases were then dried, concentrated and purified byflash chromatography [DCM : EtOAc, 1:0, 9:1] to give the title compound600 mg (99%). NMR (300 MHz) 0.8-1.0 (m, 6H), 1.0-1.8 (m, 11H), 2.2 (s,3H), 3.2 (q, 2H) 3.75 (brq, 2H), 4.3 (q, 2H), 4.75 (s, 1H), 6.7 (s, 1H),6.95 (t, 1H), 7.05 (d, 2H), 7.25 (t, 2H), 7.3 (s, 1H).

[0592] Method 19

[0593]1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0594] To1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO9616051; 600 mg, 1.29 mmol) were added DMF (5 ml) and sodiummethanethiolate (450 mg, 6.42 mmol). The reaction was then heated to 60°C. for 1 hour. The oil bath was then heated to 120° C. for 4 hours. Toquench the reaction, the temperature was lowered to room temperature andexcess acetic acid was added quickly. The reaction was kept under a flowof nitrogen through sodium hypochlorite for 2 hours. Water and EtOAcwere added and the aqueous phase was extracted three times with EtOAc.The combined organic phases were washed with water, dried andconcentrated under reduced pressure. The residue was then purified byflash chromatography [DCM : EtOAc, 9:1] to give the title compound 0.5 g(92%). NMR (400 MHz) 0.65-0.8 (m, 6H), 0.95-1.6 (m, 8h), 3.1 (q, 2H),3.6 (brq, 2H), 6.75 (s, 1H), 6.8 (t, 1H), 6.9 (d, 2H), 7.15 (t, 2H),7.55 (s, 1H).

What we claim is:
 1. A compound of formula (I):

wherein: R^(v) and R^(w) are independently selected from hydrogen orC₁₋₆alkyl; One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl andthe other is selected from C₁₋₆alkyl; R^(x) and R_(y) are independentlyselected from hydrogen or C₁₋₆alkyl, or one of R^(x) and R^(y) ishydrogen or C₁₋₆alkyl and the other is hydroxy or C₁₋₆alkoxy; R^(z) isselected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; v is 0-5; one of R⁴ and R⁵ is a group offormula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁷; X is —O—,—N(R^(a))—, —S(O)^(b)— or —CH(R^(a))—; wherein R^(a) is hydrogen orC₁₋₆alkyl and b is 0-2; Ring A is aryl or heteroaryl; wherein Ring A isoptionally substituted on carbon by one or more substituents selectedfrom R¹⁸; R⁷ is hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl;wherein R⁷ is optionally substituted on carbon by one or moresubstituents selected from R¹⁹; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R²⁰; R⁸ is hydrogen or C₁₋₆alkyl; R⁹ is hydrogen orC₁₋₆alkyl; R₁₀ is hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²¹—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²²—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁰is optionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁴; orR¹⁰ is a group of formula (IB):

wherein: R¹¹ is hydrogen or C₁₋₆alkyl; R¹² and R¹³ are independentlyselected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino,N,N—(C₁₋₁₀alkyl)₂amino, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,carbocyclyl or heterocyclyl; wherein R¹² and R¹³ may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁵; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁶; R¹⁴is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²⁷—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²⁸—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁴may be optionally substituted on carbon by one or more substituentsselected from R²⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁰; or R¹⁴ is a group of formula (IC):

R¹⁵ is hydrogen or C₁₋₆alkyl; R¹⁶ is hydrogen or C₁₋₆alkyl; wherein R¹⁶may be optionally substituted on carbon by one or more groups selectedfrom R³¹; n is 1-3; wherein the values of R⁷ may be the same ordifferent; R¹⁷, R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ are independentlyselected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,sulphamoyl, hydroxyaminocarbonyl, amidino, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,(C₁₋₁₀alkyl)₃silyl, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R³²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R³³—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁷,R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ may be independently optionallysubstituted on carbon by one or more R³⁴; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁵; R²¹, R²², R²⁷, R²⁸, R³² or R³³are independently selected from —O—, —NR³⁶—, —S(O)_(x)—, —NR³⁶C(O)NR³⁶—,—NR³⁶C(S)NR³⁶—, —OC(O)N═C—, —NR³⁶C(O)— or —C(O)NR³⁶—; wherein R³⁶ isselected from hydrogen or C₁₋₆alkyl, and x is 0-2; p, q, r and s areindependently selected from 0-2; R³⁴ is selected from halo, hydroxy,cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy,methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl,methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl,N,N-dimethylsulphamoyl, N-methylsulphamoylamino andN,N-dimethylsulphamoylamino; R²⁰, R²⁴, R²⁶, R³⁰ or R³⁵ are independentlyselected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl; or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.
 2. A compound of formula (I) asclaimed in claim 1 wherein R^(v) and R^(w) are both hydrogen, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof
 3. A compound of formula (I) as claimed in either ofclaims 1 or 2 wherein one of R¹ and R² is ethyl and the other is butyl,or R¹ and R² are both butyl, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.
 4. A compound offormula (I) as claimed in any one of claims 1-3 wherein R^(x) and R^(y)are both hydrogen, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof
 5. A compound of formula (I)as claimed in any one of claims 1-4 wherein v is 0, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.
 6. A compound of formula (I) as claimed in any one ofclaims 1-5 wherein R³ and R⁶ are both hydrogen, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof.7. A compound of formula (I) as claimed in any one of claims 1-6 whereinR⁴ is hydrogen or methylthio, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.
 8. A compound offormula (I) as claimed in any one of claims 1-7 wherein R⁵ is a group offormula (IA) as depicted above, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.
 9. A compound offormula (I) as claimed in any one of claims 1-8 wherein R⁵ is a group offormula (IA) as depicted above wherein: X is —O—; R⁷ is hydrogen; R⁸ ishydrogen; R⁹ is hydrogen; Ring A is aryl; wherein Ring A is optionallysubstituted on carbon by one or more substituents selected from R¹⁸; R¹⁰is carbamoyl or N—(C₁₋₁₀alkyl)carbamoyl or a group of formula (IB) (asdepicted above) wherein R¹⁰ is optionally substituted on carbon by oneor more substituents selected from R²³ and wherein: R¹¹ is hydrogen orC₁₋₆alkyl; R¹² and R¹³ are independently selected from hydrogen,carbamoyl or C₁₋₆alkyl; wherein R¹² and R¹³ may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁵; R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl,C₁₋₆alkyl, carbocyclyl, heterocyclyl orcarbocyclyl-(C₁₋₆alkylene)_(p)-R²⁷—(C₁₋₆alkylene)_(q)-; wherein R¹⁴ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R³⁰; orR¹⁴ is a group of formula (IC) (as depicted above) wherein: R¹⁵ ishydrogen; R¹⁶ is C₁₋₆alkyl; wherein R¹⁶ may be optionally substituted oncarbon by one or more groups selected from R³¹; n is 1; R¹⁸ is hydroxy,R²³ is hydroxy; R²⁵, R²⁹ or R³¹ are independently selected from halo,hydroxy, amino, sulphamoyl, amidino, C₁₋₆alkoxy,N,N,N—(C₁₋₆alkyl)₃ammonio, N,N—(C₁₋₆alkyl)₂sulphamoylamino,C₁₋₆alkoxycarbonylamino, carbocyclyl, heterocyclyl,carbocyclyl-(C₁₋₆alkylene)_(p)-R³²—(C₁₋₆alkylene)_(q)- orheterocyclyl-(C₁₋₆alkylene)_(r)-R³³—(C₁₋₆alkylene)_(s)-; wherein R²⁵,R²⁹ or R³¹ may be independently optionally substituted on carbon by oneor more R³⁴; and wherein if said heterocyclyl contains an —NH— group,that nitrogen may be optionally substituted by a group selected fromR³⁵; R²⁷, R³² or R³³ are independently selected from —O—,—NR³⁶C(O)NR³⁶—, —OC(O)N═C— or —NR³⁶C(O)—; wherein R²³ is hydrogen; p, q,r and s are independently selected from 0 or 1; R³⁴ is selected fromhydroxy, amino, carbamoyl, sulphamoyl or methoxy; R³⁰ or R³⁵ areindependently selected from C₁₋₆alkyl or C₁₋₆alkoxycarbonyl. or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof
 10. A compound of formula (I) (as depicted above)wherein: R^(v) and R^(w) are both hydrogen; One of R¹ and R² is ethyland the other is butyl or R¹ and R² are both butyl; R^(x) and R^(y) areboth hydrogen; v is 0; R³ and R⁶ are hydrogen; R⁴ is hydrogen ormethylthio; R⁵ is a group of formula (IA) as depicted above wherein: Xis —O—; R⁷ is hydrogen; R⁸ is hydrogen; R⁹ is hydrogen; Ring A is aryl;wherein Ring A is optionally substituted on carbon by one or moresubstituents selected from R¹⁸; R¹⁰ is carbamoyl orN—(C₁₋₁₀alkyl)carbamoyl or a group of formula (IB) (as depicted above)wherein R¹⁰ is optionally substituted on carbon by one or moresubstituents selected from R²³ and wherein: R¹¹ is hydrogen orC₁₀₋₆alkyl; R¹² and R¹³ are independently selected from hydrogen,carbamoyl or C₁₋₆alkyl; wherein R¹² and R¹³ may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁵; R¹⁴ is selected from carbamoyl, hydroxyaminocarbonyl,C₁₋₆alkyl, carbocyclyl, heterocyclyl orcarbocyclyl-(C₁₋₆alkylene)_(p)-R²⁷—(C¹⁻⁶alkylene)_(q)-; wherein R¹⁴maybe optionally substituted on carbon by one or more substituentsselected from R²⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁰; or R¹⁴ is a group of formula (IC) (as depicted above) wherein:R¹⁵ is hydrogen; R¹⁶ is C₁₋₆alkyl; wherein R¹⁶ may be optionallysubstituted on carbon by one or more groups selected from R³¹; n is 1;R¹⁸ is hydroxy; R²³ is hydroxy; R²⁵, R²⁹ or R³¹ are independentlyselected from halo, hydroxy, amino, sulphamoyl, amidino, C₁₋₆alkoxy,N,N,N—(C₁₋₆alkyl)₃ammonio, N,N—(C₁₋₆alkyl)₂sulphamoylamino,C₁₋₆alkoxycarbonylamino, carbocyclyl, heterocyclyl,carbocyclyl-(C₁₋₆alkylene)_(p)-R³²—(C₁₋₆alkylene)_(q)- orheterocyclyl-(C₁₋₆alkylene)_(r)-R³³—(C₁₋₆alkylene)_(s)-; wherein R²⁵,R²⁹ or R³¹ may be independently optionally substituted on carbon by oneor more R³⁴; and wherein if said heterocyclyl contains an —NH— group,that nitrogen may be optionally substituted by a group selected fromR³⁵; R²⁷, R³² or R³³ are independently selected from —O—,—NR³⁶C(O)NR³⁶—, —OC(O)N═C— or —NR³⁶C(O)—; wherein R²³ is hydrogen; p, q,r and s are independently selected from 0 or 1; R³⁴ is selected fromhydroxy, amino, carbamoyl, sulphamoyl or methoxy; R³⁰ or R³⁵ areindependently selected from C₁₋₆alkyl or C₁₋₆alkoxycarbonyl. or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.
 11. A compound of formula (I) selected from:1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;b1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carbamoyl-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(hydroxycarbamoyl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[2-(N′-pyrimidin-2-ylureido)ethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[2-(N′-pyridin-2-ylureido)ethyl]carbamoyl)benzyl)carbamoylmethoxy]-2,3, 4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(1-t-butoxycarbonylpiperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(N-(2,3-dihydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[2-(3,4-dihydroxyphenyl)-2-methoxyethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-((R)-α-[N′-(2-aminoethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(piperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;or1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-N,N-dimethylaminosulphamoylethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.
 12. A process for preparing a compound of formula(I), as claimed in any one of claims 1-11, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofwhich process comprises of: Process 1): oxidising a benzothiazepine offormula (II):

Process 2): for compounds of formula (I) wherein X is —O—,—NR^(a) or—S—; reacting a compound of formula (IIIa) or (IIIb):

with a compound of formula (IV):

wherein L is a displaceable group; Process 3): reacting an acid offormula (Va) or Vb):

or an activated derivative thereof; with an amine of formula (VI):

Process 4): for compounds of formula (I) wherein R¹⁰ is a group offormula (IB); reacting a compound of formula (I) wherein R¹⁰ is carboxywith an amine of formula (VII):

Process 5): for compounds of formula (I) wherein R¹⁰ is a group offormula (IB) and R¹⁴ is a group of formula (IC) reacting a compound offormula (I) wherein R¹⁴ is carboxy with an amine of formula (VIII):R¹⁵R¹⁶NH  (VIII) Process 6) for compounds of formula (I) wherein one ofR⁴ and R⁵ are independently selected from C₁₋₆alkylthio optionallysubstituted on carbon by one or more R¹⁷; reacting a compound of formula(IXa) or (IXb):

wherein L is a displaceable group; with a thiol of formula (X):R^(y)—H  (X) wherein R^(y) is C₁₋₆alkylthio optionally substituted oncarbon by one or more R¹⁶; and thereafter if necessary or desirable: i)converting a compound of the formula (I) into another compound of theformula (I); ii) removing any protecting groups; iii) forming apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug.
 13. A compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,as claimed in any one of claims 1 to 11 for use as a medicament.
 14. Acompound of formula (I), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, as claimed in any one ofclaims 1 to 11 for use in a method of prophylactic or therapeutictreatment of a warm-blooded animal, such as man.
 15. The use of acompound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as claimed in anyone of claims 1 to 11 in the manufacture of a medicament for use in theproduction of an IBAT inhibitory effect in a warm-blooded animal, suchas man.
 16. The use of a compound of the formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as claimed in any one of claims 1 to 11, in theproduction of an IBAT inhibitory effect in a warm-blooded animal, suchas man.
 17. A method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof, as claimed in any one of claims 1to
 11. 18. A pharmaceutical composition which comprises a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, as claimed in any one of claims 1 to11, in association with a pharmaceutically-acceptable diluent orcarrier.
 19. A pharmaceutical composition which comprises a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, as claimed in any one of claims 1 to11, and an HMG Co-A reductase inhibitor, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in association with a pharmaceutically acceptable diluent or carrier.20. A pharmaceutical composition which comprises a compound of formula(I), or a pharmaceutically acceptable salt, solvate, solvate of such asalt or a prodrug thereof, as claimed in any one of claims 1 to 11, anda bile acid binder, in association with a pharmaceutically acceptablediluent or carrier.
 21. A pharmaceutical composition which comprises acompound of formula (I), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, as claimed in any one ofclaims 1 to 11, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid binder in association with apharmaceutically acceptable diluent or carrier.
 22. A compositionaccording to claim 19 or claim 21 wherein the HMG Co-A reductaseinhibitor is atorvastatin, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.
 23. A compositionaccording to claim 19 or claim 21 wherein the HMG Co-A reductaseinhibitor is rosuvastatin, or a pharmaceutically acceptable saltthereof.
 24. A pharmaceutical composition which comprises a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, as claimed in any one of claims 1 to11 and a PPAR alpha and/or gamma agonist, or a pharmaceuticallyacceptable salt thereof, in association with a pharmaceuticallyacceptable diluent or carrier.
 25. A composition according to claim 24wherein the PPAR alpha and/or gamma agonist is(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoicacid or a pharmaceutically acceptable salt thereof.